thescientist--2020-08-24--FDA Gives Plasma Go-Ahead to Treat COVID-19, Experts Skeptical

President Donald Trump announced yesterday ( August 23 ) that the US Food and Drug Administration has granted emergency use authorization for the use of convalescent plasma to treat COVID-19 , a disease that has so far killed more than 170,000 people in the US .
“ To deliver treatments and vaccines , we ’ re removing unnecessary barriers and delays , not by cutting corners , but by marshaling the full power of the federal government , ” Trump said at a press conference announcing the decision .
“ Based on the science and the data the FDA has @ @ @ @ @ @ @ is safe and very effective.
” While he hailed the new treatment as a “ major breakthrough , ” the scientific community has largely reacted with skepticism , in part because the authorization was based on a handful of studies from the Mayo Clinic that failed to include appropriate randomization and controls .
“ I watched this in horror , ” Eric Topol , a physician and director of the Scripps Research Translational Institute , tells The Washington Post .
“ These are basically just exploratory analyses that don ’ t prove anything @ @ @ @ @ @ @ declare this as a breakthrough .
.
.
.
All this does is jeopardize ever getting the truth.
” Harlan Krumholz , the director of the Center for Outcomes Research and Evaluation at Yale New Haven Hospital , similarly tells STAT the FDA ’ s decision “ raises the question of what strength of evidence is necessary to treat during a pandemic.
” The new authorization stems from both the historical use of plasma as a safe treatment and a series of studies testing the safety of plasma given to COVID-19 patients .
@ @ @ @ @ @ @ from COVID-19 contains antibodies capable of fighting the virus .
When administered to those in the grips of the disease , it could in theory help patients survive until their own immune systems can produce the needed antibodies , as has been shown with other diseases .
In June , the Mayo Clinic released data detailing the safety of plasma given to 20,000 patients , including a high percentage of women and underrepresented minorities .
While the results suggested that plasma is safe , the authors reported at the time that “ this @ @ @ @ @ @ @ effectiveness of convalescent plasma for treating COVID-19.
” More recently , the Mayo Clinic completed an additional study—released on the preprint server MedRxiv without peer review—involving more than 35,000 additional patients .
Adults in the hospital for critical cases of COVID-19 received transfusions of plasma .
Those who received the plasma within three days of their diagnosis had a seven-day death rate of 8.7 percent , while those who received the infusion four days after diagnosis died at a rate of 11.9 percent .
Both studies failed to include a placebo group , @ @ @ @ @ @ @ the therapy truly worked .
In addition , none were randomized—patients in each study knew they were going to receive plasma .
The Mayo Clinic studies are part of an “ expanded access ” program launched in April to increase the availability of the treatment rather than to assess its effectiveness .
The program , which has ballooned since its inception , has done so in the absence of concrete recommendations from any leading health agency , and there are fears that a run on plasma could use up supplies .
US hospitals @ @ @ @ @ @ @ a day with blood infusions of plasma , Buzzfeed News reports , totaling more than 70,000 people .
The New York Times reported August 19 , prior to the emergency use authorization ( EUA ) , that several experts , including National Institutes of Health Director Francis Collins and National Institute of Allergy and Infectious Diseases ( NIAID ) Director Anthony Fauci , urged the FDA to reconsider given the relative weakness of the Mayo Clinic results .
“ The three of us are pretty aligned on the importance of robust data through @ @ @ @ @ @ @ pandemic does not change that , ” Deputy Director for Clinical Research and Special Projects at NIAID , Clifford Lane , tells The Times .
In response to the FDA ’ s announcement , the World Health Organization ( WHO ) issued a statement urging caution over the effectiveness of plasma , Reuters reports .
“ There are a number of clinical trials going on around the world looking at convalescent plasma compared to the standard of care , ” Soumya Swaminathan , the WHO ’ s chief scientist , said in a @ @ @ @ @ @ @ of them have actually reported interim results .
.
.
and at the moment , it ’ s still very low-quality evidence.
” The FDA acknowledges the limitations of the intervention in the supporting EUA documentation .
Denise Hinton , the chief scientist for the FDA , stated , “ COVID-19 convalescent plasma should not be considered a new standard of care for the treatment of patients with COVID-19 .
Additional data will be forthcoming from other analyses and ongoing , well-controlled clinical trials in the coming months.
” But some experts , @ @ @ @ @ @ @ of medicine at the University of Pennsylvania , says she worries the widespread use of plasma will dissuade patients from voluntarily enrolling in these robust clinical trials , where they are randomly assigned to treatment groups that could result in them receiving a placebo .
“ I just think logistically it ’ s going to be very challenging , ” Bar tells Buzzfeed .

ABOVE: © ISTOCK.COM, NIKOLA STOJADINOVIC
President Donald Trump announced yesterday (August 23) that the US Food and Drug Administration has granted emergency use authorization for the use of convalescent plasma to treat COVID-19, a disease that has so far killed more than 170,000 people in the US.
“To deliver treatments and vaccines, we’re removing unnecessary barriers and delays, not by cutting corners, but by marshaling the full power of the federal government,” Trump said at a press conference announcing the decision. “Based on the science and the data the FDA has made the independent determination that the treatment is safe and very effective.”
While he hailed the new treatment as a “major breakthrough,” the scientific community has largely reacted with skepticism, in part because the authorization was based on a handful of studies from the Mayo Clinic that failed to include appropriate randomization and controls.
“I watched this in horror,” Eric Topol, a physician and director of the Scripps Research Translational Institute, tells The Washington Post. “These are basically just exploratory analyses that don’t prove anything. It’s just extraordinary to declare this as a breakthrough. . . . All this does is jeopardize ever getting the truth.”
Harlan Krumholz, the director of the Center for Outcomes Research and Evaluation at Yale New Haven Hospital, similarly tells STAT the FDA’s decision “raises the question of what strength of evidence is necessary to treat during a pandemic.”
The new authorization stems from both the historical use of plasma as a safe treatment and a series of studies testing the safety of plasma given to COVID-19 patients. The plasma of people who have recovered from COVID-19 contains antibodies capable of fighting the virus. When administered to those in the grips of the disease, it could in theory help patients survive until their own immune systems can produce the needed antibodies, as has been shown with other diseases.
In June, the Mayo Clinic released data detailing the safety of plasma given to 20,000 patients, including a high percentage of women and underrepresented minorities. While the results suggested that plasma is safe, the authors reported at the time that “this alone does not provide any evidence on effectiveness of convalescent plasma for treating COVID-19.”
More recently, the Mayo Clinic completed an additional study—released on the preprint server MedRxiv without peer review—involving more than 35,000 additional patients. Adults in the hospital for critical cases of COVID-19 received transfusions of plasma. Those who received the plasma within three days of their diagnosis had a seven-day death rate of 8.7 percent, while those who received the infusion four days after diagnosis died at a rate of 11.9 percent.
Both studies failed to include a placebo group, making it difficult to assess how well the therapy truly worked. In addition, none were randomized—patients in each study knew they were going to receive plasma.
The Mayo Clinic studies are part of an “expanded access” program launched in April to increase the availability of the treatment rather than to assess its effectiveness. The program, which has ballooned since its inception, has done so in the absence of concrete recommendations from any leading health agency, and there are fears that a run on plasma could use up supplies. US hospitals are currently treating around 1,500 COVID-19 patients a day with blood infusions of plasma, Buzzfeed News reports, totaling more than 70,000 people.
The New York Times reported August 19, prior to the emergency use authorization (EUA), that several experts, including National Institutes of Health Director Francis Collins and National Institute of Allergy and Infectious Diseases (NIAID) Director Anthony Fauci, urged the FDA to reconsider given the relative weakness of the Mayo Clinic results. “The three of us are pretty aligned on the importance of robust data through randomized control trials, and that a pandemic does not change that,” Deputy Director for Clinical Research and Special Projects at NIAID, Clifford Lane, tells The Times.
In response to the FDA’s announcement, the World Health Organization (WHO) issued a statement urging caution over the effectiveness of plasma, Reuters reports. “There are a number of clinical trials going on around the world looking at convalescent plasma compared to the standard of care,” Soumya Swaminathan, the WHO’s chief scientist, said in a news conference. “Only a few of them have actually reported interim results . . . and at the moment, it’s still very low-quality evidence.”
The FDA acknowledges the limitations of the intervention in the supporting EUA documentation. Denise Hinton, the chief scientist for the FDA, stated, “COVID-19 convalescent plasma should not be considered a new standard of care for the treatment of patients with COVID-19. Additional data will be forthcoming from other analyses and ongoing, well-controlled clinical trials in the coming months.”
But some experts, including Katharine Bar, an assistant professor of medicine at the University of Pennsylvania, says she worries the widespread use of plasma will dissuade patients from voluntarily enrolling in these robust clinical trials, where they are randomly assigned to treatment groups that could result in them receiving a placebo. “I just think logistically it’s going to be very challenging,” Bar tells Buzzfeed.


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thescientist--2020-08-27--Zika Infection Increases Risk of Severe Dengue Fever

The 2015–16 Zika virus epidemic that spread through Central and South America was followed last year by a surge in dengue virus cases .
While this unfortunate series of diseases battered the region ’ s populace , it gave scientists , who had been following a cohort of several thousand children in the area , the opportunity to study how these two flaviviruses might jointly affect the immune system .
That research has revealed that kids infected with dengue virus are more likely to suffer worse symptoms if they had previously been infected with Zika than if they hadn ’ @ @ @ @ @ @ @ Science today ( August 27 ) , indicate that antibody-dependent enhancement—a phenomenon known for making a second infection with a virus worse than the first—is not limited to influencing infections by the same pathogen .
This raises concerns that such cross-species effects may occur for other types of viruses—including coronaviruses—and may impact vaccine safety , scientists say .
“ It ’ s a pretty amazing story .
[ It ] addresses what I think is the most important question in the field that has emerged following the Zika virus outbreak , and that @ @ @ @ @ @ @ dengue virus influence each other ?
” says virologist Jean Lim of the Icahn School of Medicine at Mount Sinai who was not part of the research team .
Dengue and Zika viruses are closely related members of the flavivirus genus and are both transmitted to humans via the bites of infected mosquitoes .
Dengue virus infection can be asymptomatic or can cause symptoms such as fever , headache , muscle aches , and rash .
In some cases the disease can be severe , causing hemorrhagic fever and even shock ( a @ @ @ @ @ @ @ Zika virus causes a mostly mild disease—characterized by fever , rash , and joint pain—that resolves within a week , but in adults it can occasionally cause Guillain-Barré syndrome , an autoimmune condition affecting the peripheral nerves , and in pregnant women , the virus can lead to brain defects in the developing fetus including microcephaly .
There are four strains , or serotypes , of dengue virus and infection by one type has a curious effect on infection by another , explains epidemiologist Isabel Rodriguez-Barraquer of the University of California ( UC @ @ @ @ @ @ @ did not work on the project .
While an infection with the same serotype twice will not cause disease the second time around , if a different serotype causes the second infection , the existing antibodies fail to neutralize the virus and actually assist its entry into host cells .
“ The antibodies that your body builds after that first infection make the second infection worse and that ’ s often referred to as antibody-dependent enhancement , ” Rodriquez-Barraquer says .
This phenomenon is also thought to explain the worsening of disease severity @ @ @ @ @ @ @ is closely related to dengue , “ when Zika came along there was a question [ of whether ] there was going to be some sort of immunological interaction , ” says UC Berkeley ’ s Eva Harris .
And her group was in a perfect position to provide an answer , she adds , thanks to a long-standing collaboration with scientists in Nicaragua who have been monitoring infections , measuring antibody titers , and collecting other data from a rolling cohort of children since 2004 .
In an earlier study , Harris @ @ @ @ @ @ @ infections preceding the Zika outbreak that started in 2015 offered a slightly protective effect against Zika severity , at least in children .
Then , in 2019 , when a major epidemic of dengue infections blew through the region—the worst in Nicaragua ’ s history—the group looked at the reverse scenario : whether prior Zika infection influenced dengue severity .
A total of 302 children of a cohort of 3,434 were diagnosed with symptomatic dengue fever between 2019 and 2020 , confirmed via PCR amplification of the virus ’ s genetic material .
@ @ @ @ @ @ @ cohort , the team then calculated that children who had had a prior Zika infection had a roughly 12 percent chance of developing symptomatic dengue , compared with an only a 3.5 percent chance for children that had had no prior flavivirus exposure .
Children who had had one prior dengue infection had a roughly 9 percent chance of later symptomatic disease .
Prior Zika or dengue infection also increased the risk that a child would experience the most severe symptoms of dengue—hemorrhagic fever and shock—compared with children who had not previously had @ @ @ @ @ @ @ The researchers went on to investigate how antibody titers resulting from previous Zika or dengue infection influenced later dengue outcomes .
They found that individuals with very high or very low anti-Zika or anti-dengue antibodies were better protected against dengue than those with intermediate titers .
These results suggested that high levels of antibodies , as might occur in the immediate aftermath of acute infection might be protective , but that once titers begin to drop , the phenomenon of antibody-dependent enhancement can kick in .
At very low titers , it seems @ @ @ @ @ @ @ to cause that boost in disease severity .
`` The study is significant because for the first time it establishes that the sequence relationship between Zika and different dengue virus serotype infections impacts disease outcome , ” Michael Diamond , an infectious disease researcher at Washington University School of Medicine in St Louis who also did not work on the project , writes in an email to The Scientist .
“ Whereas prior dengue infection appears to have neutral or modest protective effects against subsequent Zika infection , ” he says , the @ @ @ @ @ @ @ infection can predispose to more severe infection and disease caused by dengue.
” In conclusion , says Lim , “ data like this are certainly worrisome , particularly for individuals living in areas where dengue and Zika both circulate.
” Moreover , she says , the implication is that , much like the dengue vaccine , “ a stand-alone Zika virus vaccine may put a person at risk for increased dengue virus disease [ severity ] .
” Antibody-dependent enhancement of infection is not unique to dengue , having been reported in certain @ @ @ @ @ @ @ humans , says Rodriguez-Barraquer .
“ One of the questions right now that is still open is whether something similar could happen between SARS-CoV-2 and the other coronaviruses , ” she says .
While this is something to bear in mind , especially for vaccine development , she says , “ there ’ s no evidence yet that that is happening , fortunately .
”

ABOVE: ©ISTOCK, MEMBIO
The 2015–16 Zika virus epidemic that spread through Central and South America was followed last year by a surge in dengue virus cases. While this unfortunate series of diseases battered the region’s populace, it gave scientists, who had been following a cohort of several thousand children in the area, the opportunity to study how these two flaviviruses might jointly affect the immune system. That research has revealed that kids infected with dengue virus are more likely to suffer worse symptoms if they had previously been infected with Zika than if they hadn’t.
The findings, reported in Science today (August 27), indicate that antibody-dependent enhancement—a phenomenon known for making a second infection with a virus worse than the first—is not limited to influencing infections by the same pathogen. This raises concerns that such cross-species effects may occur for other types of viruses—including coronaviruses—and may impact vaccine safety, scientists say.
“It’s a pretty amazing story. [It] addresses what I think is the most important question in the field that has emerged following the Zika virus outbreak, and that is, how do Zika virus and dengue virus influence each other?” says virologist Jean Lim of the Icahn School of Medicine at Mount Sinai who was not part of the research team.
Dengue and Zika viruses are closely related members of the flavivirus genus and are both transmitted to humans via the bites of infected mosquitoes. Dengue virus infection can be asymptomatic or can cause symptoms such as fever, headache, muscle aches, and rash. In some cases the disease can be severe, causing hemorrhagic fever and even shock (a dangerous drop in blood pressure). Zika virus causes a mostly mild disease—characterized by fever, rash, and joint pain—that resolves within a week, but in adults it can occasionally cause Guillain-Barré syndrome, an autoimmune condition affecting the peripheral nerves, and in pregnant women, the virus can lead to brain defects in the developing fetus including microcephaly.
There are four strains, or serotypes, of dengue virus and infection by one type has a curious effect on infection by another, explains epidemiologist Isabel Rodriguez-Barraquer of the University of California (UC), San Francisco, who also did not work on the project. While an infection with the same serotype twice will not cause disease the second time around, if a different serotype causes the second infection, the existing antibodies fail to neutralize the virus and actually assist its entry into host cells. “The antibodies that your body builds after that first infection make the second infection worse and that’s often referred to as antibody-dependent enhancement,” Rodriquez-Barraquer says. This phenomenon is also thought to explain the worsening of disease severity seen after dengue vaccination.
Because Zika is closely related to dengue, “when Zika came along there was a question [of whether] there was going to be some sort of immunological interaction,” says UC Berkeley’s Eva Harris. And her group was in a perfect position to provide an answer, she adds, thanks to a long-standing collaboration with scientists in Nicaragua who have been monitoring infections, measuring antibody titers, and collecting other data from a rolling cohort of children since 2004.
In an earlier study, Harris’s group had shown that dengue infections preceding the Zika outbreak that started in 2015 offered a slightly protective effect against Zika severity, at least in children. Then, in 2019, when a major epidemic of dengue infections blew through the region—the worst in Nicaragua’s history—the group looked at the reverse scenario: whether prior Zika infection influenced dengue severity.
A total of 302 children of a cohort of 3,434 were diagnosed with symptomatic dengue fever between 2019 and 2020, confirmed via PCR amplification of the virus’s genetic material. By analyzing the infection history of the cohort, the team then calculated that children who had had a prior Zika infection had a roughly 12 percent chance of developing symptomatic dengue, compared with an only a 3.5 percent chance for children that had had no prior flavivirus exposure. Children who had had one prior dengue infection had a roughly 9 percent chance of later symptomatic disease.
Prior Zika or dengue infection also increased the risk that a child would experience the most severe symptoms of dengue—hemorrhagic fever and shock—compared with children who had not previously had flavivirus disease, the team showed.
The researchers went on to investigate how antibody titers resulting from previous Zika or dengue infection influenced later dengue outcomes. They found that individuals with very high or very low anti-Zika or anti-dengue antibodies were better protected against dengue than those with intermediate titers. These results suggested that high levels of antibodies, as might occur in the immediate aftermath of acute infection might be protective, but that once titers begin to drop, the phenomenon of antibody-dependent enhancement can kick in. At very low titers, it seems, the antibodies are no longer able to cause that boost in disease severity.
"The study is significant because for the first time it establishes that the sequence relationship between Zika and different dengue virus serotype infections impacts disease outcome,” Michael Diamond, an infectious disease researcher at Washington University School of Medicine in St Louis who also did not work on the project, writes in an email to The Scientist. “Whereas prior dengue infection appears to have neutral or modest protective effects against subsequent Zika infection,” he says, the study shows that “pre-existing Zika virus infection can predispose to more severe infection and disease caused by dengue.”
In conclusion, says Lim, “data like this are certainly worrisome, particularly for individuals living in areas where dengue and Zika both circulate.” Moreover, she says, the implication is that, much like the dengue vaccine, “a stand-alone Zika virus vaccine may put a person at risk for increased dengue virus disease [severity].”
Antibody-dependent enhancement of infection is not unique to dengue, having been reported in certain coronaviruses too—though not those known to infect humans, says Rodriguez-Barraquer. “One of the questions right now that is still open is whether something similar could happen between SARS-CoV-2 and the other coronaviruses,” she says. While this is something to bear in mind, especially for vaccine development, she says, “there’s no evidence yet that that is happening, fortunately.”
L.C. Katzelnick et al., “Zika virus infection enhances future risk of severe dengue disease,” Science, 369:1123–28, 2020.


thescientist--2020-08-26--Modeling Study Flags Species Susceptible to SARS-CoV-2

An international team of scientists has assessed the fit for the main cellular attachment point of SARS-CoV-2 in 410 species of vertebrates , including 252 mammals , to categorize those most susceptible to viral entry .
The computational study , published in PNAS Monday ( August 24 ) , predicts that several critically endangered primate species are at very high risk of the virus , although the results need to be confirmed with further experiments or surveillance .
The receptor for the virus—angiotensin converting enzyme-2 , or ACE2—is found in many types of cells and tissues , including in the @ @ @ @ @ @ @ people .
The spike protein that studs the exterior of the viral particle can be compared to a key , ACE2 a lock .
In people , 25 amino acids of the enzyme are important for the virus to gain entry into cells .
The scientists behind this latest study used these amino acid sequences to evaluate how suitable the ACE2 protein is for SARS-CoV-2 in other species , for which high quality sequence data for ACE2 existed .
The researchers developed an index that weighted overall amino acid similarity with the residues @ @ @ @ @ @ @ for binding SARS-CoV-2 , says senior author Harris Lewin of the University of California , Davis .
The results spotlighted primates such as the Western lowland gorilla , Sumatran orangutan , chimpanzee , and bonobo as at very high risk of infection .
This was not unexpected , given that their ACE2 sequence is identical to our own .
Monkeys , which are mostly also pegged as very high risk , are known to be vulnerable to COVID-19 and have been used to study the disease , allowing scientists to ask questions about @ @ @ @ @ @ @ taking steps since early on in the pandemic to protect their animals from the disease .
The second category ( high risk ) contained a few surprises , such as three deer species , muskrat , Chinese hamster , and Gambian pouched rat .
The similarities for many of these evolutionarily distant taxa “ is just an evolutionary quirk , ” says Lewin .
Also in that category were numerous marine mammals , such as the gray whale , minke whale , harbour porpoise , killer whale , narwhal , and common bottlenose @ @ @ @ @ @ @ species between bats and humans it is likely in the two highest risk categories , which include fewer than 100 species , according to Lewin .
He is especially interested in hamsters having compatible ACE2 receptors for SARS-CoV-2 and says wild hamsters might be worth investigating as possible intermediate hosts for transmission of SARS-CoV-2 from bats to humans .
Indeed , the Syrian hamster has recently been shown to be a good model for COVID-19 research .
Domestic animals such as cats , cattle , and sheep were at medium risk , and @ @ @ @ @ @ @ at low risk for ACE2 binding .
“ Ferrets and mink were in the low risk category , and they have been shown to be susceptible experimentally , ” says Lewin .
“ There ’ s something we don ’ t understand about those species.
” It could be that the virus uses a receptor other than ACE2 , or that even low-affinity connections and high viral dose can lead to infection .
Lewin says the next step now is to infect cells of various species with the virus and to do careful @ @ @ @ @ @ @ What ’ s nice is that they looked at a wide range of different species , ” says Fabian Leendertz , an infectious disease scientist at the Robert Koch Institute in Berlin .
He warns that the results give hints of susceptibility , rather than solid evidence to guide management decisions for places such as zoos .
Actual risks can only be confirmed with additional experimental results .
Leendertz was unsurprised that great apes are susceptible , and had warned in March that they are at risk from COVID-19 .
Another research group @ @ @ @ @ @ @ 35 marine mammals , again based on how well their ACE2 interacts with the viral spike protein in computer models .
They predicted that 15 species would be susceptible .
These studies “ can not predict the outcome of infection , but can predict susceptibility to infection , ” explains Graham Dellaire , a molecular biologist at Dalhousie University in Canada , who coauthored the study , posted to bioRxiv August 14 .
“ There are also mitigating circumstances that can make the infection worse or milder in any given organism.
” For @ @ @ @ @ @ @ ACE2 enzymes in nasopharynx or lung tissues , critical locations for COVID-19 infection and transmission in humans .
For many species , wild or in captivity , it would not be ethical or appropriate to infect them with SARS-CoV-2 in order to observe the outcome .
Instead , studies of the ACE2 receptor can flag which species we need to be monitored as potentially vulnerable to infection .
It can also inspire cell infectivity experiments .
“ We should be more aware in the context of zoos and aquariums about human interactions with @ @ @ @ @ @ @ “ In zoos , we don ’ t know the consequences of animals getting infected .
It could be mild or it could be multi-organ necrosis.
” Those who come into close contact with wild animals should also take precautions .
Dellaire warns that sewage discharge into marine environments could expose marine mammals to SARS-CoV-2 .
There ’ s some evidence that the virus might survive for more than 10 days at sea , he adds , and contaminated wastewater could concentrate in tidal pools .
RNA from the virus can be detected @ @ @ @ @ @ @ as a way of monitoring COVID-19 in communities .
Lewin says cruise ships need to take extra precautions in discharging sewage at sea .
Many mammal species live in groups , which heightens the risks for them .
“ Whales and dolphins are in pods and are highly social .
With one animal infected , the virus could spread and then adapt and remain in that population , ” Dellaire warns .

ABOVE: Western lowland gorilla
SKIP BROWN/SMITHSONIAN’S NATIONAL ZOO AND CONSERVATION BIOLOGY INSTITUTE
An international team of scientists has assessed the fit for the main cellular attachment point of SARS-CoV-2 in 410 species of vertebrates, including 252 mammals, to categorize those most susceptible to viral entry. The computational study, published in PNAS Monday (August 24), predicts that several critically endangered primate species are at very high risk of the virus, although the results need to be confirmed with further experiments or surveillance.
The receptor for the virus—angiotensin converting enzyme-2, or ACE2—is found in many types of cells and tissues, including in the nose, mouth, and lungs of people. The spike protein that studs the exterior of the viral particle can be compared to a key, ACE2 a lock.
In people, 25 amino acids of the enzyme are important for the virus to gain entry into cells. The scientists behind this latest study used these amino acid sequences to evaluate how suitable the ACE2 protein is for SARS-CoV-2 in other species, for which high quality sequence data for ACE2 existed.
The researchers developed an index that weighted overall amino acid similarity with the residues in human ACE2 known to be important for binding SARS-CoV-2, says senior author Harris Lewin of the University of California, Davis.
The results spotlighted primates such as the Western lowland gorilla, Sumatran orangutan, chimpanzee, and bonobo as at very high risk of infection. This was not unexpected, given that their ACE2 sequence is identical to our own. Monkeys, which are mostly also pegged as very high risk, are known to be vulnerable to COVID-19 and have been used to study the disease, allowing scientists to ask questions about immune memory. Primate facilities have been taking steps since early on in the pandemic to protect their animals from the disease.
The second category (high risk) contained a few surprises, such as three deer species, muskrat, Chinese hamster, and Gambian pouched rat. The similarities for many of these evolutionarily distant taxa “is just an evolutionary quirk,” says Lewin. Also in that category were numerous marine mammals, such as the gray whale, minke whale, harbour porpoise, killer whale, narwhal, and common bottlenose dolphin.
A new genomic study from UC Davis ranks the potential of the SARS-CoV-2 spike protein to bind to the ACE2 receptor site in 410 vertebrate animals. matthew verdolivo/uc davis
If there is an intermediate species between bats and humans it is likely in the two highest risk categories, which include fewer than 100 species, according to Lewin. He is especially interested in hamsters having compatible ACE2 receptors for SARS-CoV-2 and says wild hamsters might be worth investigating as possible intermediate hosts for transmission of SARS-CoV-2 from bats to humans. Indeed, the Syrian hamster has recently been shown to be a good model for COVID-19 research.
Domestic animals such as cats, cattle, and sheep were at medium risk, and dogs, horses, and pigs were at low risk for ACE2 binding. “Ferrets and mink were in the low risk category, and they have been shown to be susceptible experimentally,” says Lewin. “There’s something we don’t understand about those species.”
It could be that the virus uses a receptor other than ACE2, or that even low-affinity connections and high viral dose can lead to infection. Lewin says the next step now is to infect cells of various species with the virus and to do careful challenge studies with live animals.
“What’s nice is that they looked at a wide range of different species,” says Fabian Leendertz, an infectious disease scientist at the Robert Koch Institute in Berlin. He warns that the results give hints of susceptibility, rather than solid evidence to guide management decisions for places such as zoos. Actual risks can only be confirmed with additional experimental results.
Leendertz was unsurprised that great apes are susceptible, and had warned in March that they are at risk from COVID-19.
Another research group investigated the susceptibility to SARS-CoV-2 infection of 35 marine mammals, again based on how well their ACE2 interacts with the viral spike protein in computer models. They predicted that 15 species would be susceptible.
These studies “cannot predict the outcome of infection, but can predict susceptibility to infection,” explains Graham Dellaire, a molecular biologist at Dalhousie University in Canada, who coauthored the study, posted to bioRxiv August 14. “There are also mitigating circumstances that can make the infection worse or milder in any given organism.” For example, some species might not have ACE2 enzymes in nasopharynx or lung tissues, critical locations for COVID-19 infection and transmission in humans.
For many species, wild or in captivity, it would not be ethical or appropriate to infect them with SARS-CoV-2 in order to observe the outcome. Instead, studies of the ACE2 receptor can flag which species we need to be monitored as potentially vulnerable to infection. It can also inspire cell infectivity experiments.
“We should be more aware in the context of zoos and aquariums about human interactions with these animals,” says Dellaire. “In zoos, we don’t know the consequences of animals getting infected. It could be mild or it could be multi-organ necrosis.” Those who come into close contact with wild animals should also take precautions.
Dellaire warns that sewage discharge into marine environments could expose marine mammals to SARS-CoV-2. There’s some evidence that the virus might survive for more than 10 days at sea, he adds, and contaminated wastewater could concentrate in tidal pools.
RNA from the virus can be detected in wastewater and has even been suggested as a way of monitoring COVID-19 in communities. Lewin says cruise ships need to take extra precautions in discharging sewage at sea.
Many mammal species live in groups, which heightens the risks for them. “Whales and dolphins are in pods and are highly social. With one animal infected, the virus could spread and then adapt and remain in that population,” Dellaire warns.


thescientist--2020-08-26--Is a Bradykinin Storm Brewing in COVID-19?

ABOVE : A hyperactive bradykinin system permits fluid , shown in yellow , to leak out of a blood vessel and allows immune cells , shown in purple , to squeeze out as well .
JASON SMITH/ORNL , US DEPARTMENT OF ENERGY On a Sunday afternoon in mid-April this year , Daniel Jacobson , a computational systems biologist at Oak Ridge National Laboratory in Tennessee , was looking at gene expression data from the lung fluid of COVID-19 patients on his computer screen when he spotted something striking—the expression of genes for key enzymes in the renin-angiotensin system ( RAS @ @ @ @ @ @ @ and fluid balance , was askew .
Jacobson followed this abnormal RAS in the lung fluid samples to the kinin cascade , an inflammatory pathway that is tightly regulated by the RAS .
He found that the kinin system—in which a key peptide , bradykinin , causes blood vessels to leak and fluid to accumulate in tissues and organs—was thrown out of balance as well in COVID-19 patients .
Infected individuals showed heightened expression of genes for the bradykinin receptors , as well as for enzymes called kallikreins that activate the kinin pathway @ @ @ @ @ @ @ , published July 7 in eLife , could perhaps explain the abnormal accumulation of fluid in the lungs that is so common in COVID-19 patients , the authors say .
Unbeknownst to Jacobson , Frank van de Veerdonk , an infectious disease specialist at the Radboud University Medical Center in the Netherlands , was heading down the same molecular pathway in mid-March .
He had noticed two features in COVID-19 patients in his clinic—fluid in the lungs and inflammation .
Because other labs had pegged angiotensin-converting enzyme-2 ( ACE2 ) , a key @ @ @ @ @ @ @ the SARS-CoV-2 receptor , and because he knew that ACE2 regulates the kinin system , van de Veerdonk began connecting the dots .
In April , he and his group hypothesized that a dysregulated bradykinin system was leading to leaky blood vessels in the lungs and perhaps causing excess fluid to build up .
See “ Receptors for SARS-CoV-2 Present in Wide Variety of Human Cells ” Josef Penninger , director of the Life Sciences Institute at the University of British Columbia in Vancouver who discovered that ACE2 is the essential in vivo @ @ @ @ @ @ @ that he is convinced that bradykinin plays a role in COVID-19 pathogenesis .
“ It does make a lot of sense.
” He adds that Jacobson ’ s study lends support to the hypothesis , but further confirmation is needed .
“ Gene expression signatures don ’ t tell us the whole story .
I think it is very important to actually measure the proteins.
” van de Veerdonk recognizes that peptide levels need to be measured and is currently setting up mass spectrometry to measure kinins in the plasma , which have @ @ @ @ @ @ @ few seconds .
In the meantime , Jacobson and his coauthors advocate in their paper for targeting the bradykinin pathway to counter the excess fluid present in the lungs of COVID-19 patients .
As there are already a couple of approved drugs that can interfere with the kinin pathway , doctors have begun deploying them in a number of clinical trials .
A common theme that underpins many of the disease manifestations of COVID-19 , such as acute respiratory distress syndrome ( ARDS ) , is inflammation and edema , or fluid build-up @ @ @ @ @ @ @ vessels , immune cells ( as well as the cytokines and other molecules produced by them ) , and plasma proteins such as clotting factors , bradykinin , and other kinins assume center stage in this spectacle of acute inflammation .
Activation of the kinin system in the context of blood clotting—which can be dysregulated in some COVID-19 patients—generates bradykinin and related peptides through two distinct pathways : the plasma kallikrein pathway ( activated by a clotting factor called the Hageman factor ) and the tissue kallikrein pathway ( activated by tissue enzymes @ @ @ @ @ @ @ fibrinolytic system that breaks down clots in the bloodstream ) .
Bradykinin is then converted to des-Arg9-bradykinin ( DABK ) .
When bradykinin and DABK bind to their corresponding receptors , B R and B R , respectively , fluid begins to leak from blood vessels .
The RAS pathway tightly controls the kinin system .
ACE breaks down bradykinin , while ACE2 breaks down DABK .
ACE and ACE2 therefore act as regulatory brakes in the kinin system .
But because ACE2 combines with SARS and SARS-CoV-2 and is internalized into the @ @ @ @ @ @ @ the enzyme might drop , and , according to van de Veerdonk ’ s hypothesis , the bradykinin cascade then goes into overdrive .
“ As part of the explanation of COVID pathophysiology , it makes perfect sense , but it ’ s one piece of a very large and complex puzzle and it only partly helps us explain and understand better a very difficult disease , ” says David Fedson , a retired general internist who is interested in developing treatments for pathogens that cause pandemics .
Now it ’ s up @ @ @ @ @ @ @ ask , “ how is that meaningful and what can I do about it ?
—which is the most important question.
” Penninger , who is the founder of a company that is testing ACE2 as a treatment for lung failure in a Phase 2 trial in COVID-19 patients , agrees .
Currently , there are two approved drugs that target the kinin system : icatibant ( a B R blocker ) and the monoclonal antibody lanadelumab , which inhibits plasma kallikrein ( there are no drugs yet approved that inhibit tissue kallikrein @ @ @ @ @ @ @ targeting the kinin system early in the disease , soon after a patient is hospitalized , and is hypoxic , but hasn ’ t yet developed ARDS , might be helpful .
That is what his group found in a small exploratory study published this month .
COVID-19 patients taking icatibant showed marked improvement in oxygenation as evidenced by a substantial decrease in need for supplemental oxygen , compared to control patients .
Allen Kaplan , a professor at the Medical University of South Carolina and an expert on bradykinin who was not @ @ @ @ @ @ @ Scientist that this preliminary observation supports the idea that icatibant might be helpful “ and should therefore be studied in a double-blind placebo-controlled fashion [ in COVID patients ] .
” Another multicenter randomized clinical trial in the US is testing icatibant in critically ill COVID-19 patients in the ICU .
A clinical trial in Cleveland is testing lanadelumab in COVID-19 patients with pneumonia .
van de Veerdonk ’ s group is also testing the plasma kallikrein inhibitor ( which is being supplied by Takeda , a company that also manufactures icatibant ) @ @ @ @ @ @ @ Netherlands in hospitalized COVID-19 patients receiving supplemental oxygen , to see whether the drug decreases the need for oxygen .
If all goes well for van de Veerdonk and his team , lanadelumab will be integrated into the REMAP-CAP trial that is evaluating several drugs for community-acquired pneumonia in thousands of patients across several countries and includes COVID-19 patients in one arm .
Kaplan has his reservations , and notes that using the monoclonal antibody against plasma kallikrein in COVID-19 could be interesting , but if it turns out that tissue kallikrein is @ @ @ @ @ @ @ won ’ t work .
Clarification ( August 27 ) : The seventh paragraph initially indicated that van de Veerdonk is currently using mass spectrometry to measure kallikreins in the plasma of COVID-19 patients and that it was impossible to do the same for bradykinin , which has a half-life in plasma of just a few seconds .
This has now been changed to clarify that van de Veerdonk is currently setting up mass spectrometry to measure kinins in the plasma , which have a very short half-life .

ABOVE: A hyperactive bradykinin system permits fluid, shown in yellow, to leak out of a blood vessel and allows immune cells, shown in purple, to squeeze out as well.
JASON SMITH/ORNL, US DEPARTMENT OF ENERGY
On a Sunday afternoon in mid-April this year, Daniel Jacobson, a computational systems biologist at Oak Ridge National Laboratory in Tennessee, was looking at gene expression data from the lung fluid of COVID-19 patients on his computer screen when he spotted something striking—the expression of genes for key enzymes in the renin-angiotensin system (RAS), involved in blood pressure regulation and fluid balance, was askew.
Jacobson followed this abnormal RAS in the lung fluid samples to the kinin cascade, an inflammatory pathway that is tightly regulated by the RAS. He found that the kinin system—in which a key peptide, bradykinin, causes blood vessels to leak and fluid to accumulate in tissues and organs—was thrown out of balance as well in COVID-19 patients. Infected individuals showed heightened expression of genes for the bradykinin receptors, as well as for enzymes called kallikreins that activate the kinin pathway, compared with controls.
The results, published July 7 in eLife, could perhaps explain the abnormal accumulation of fluid in the lungs that is so common in COVID-19 patients, the authors say.
Unbeknownst to Jacobson, Frank van de Veerdonk, an infectious disease specialist at the Radboud University Medical Center in the Netherlands, was heading down the same molecular pathway in mid-March. He had noticed two features in COVID-19 patients in his clinic—fluid in the lungs and inflammation. Because other labs had pegged angiotensin-converting enzyme-2 (ACE2), a key enzyme in the RAS, as being the SARS-CoV-2 receptor, and because he knew that ACE2 regulates the kinin system, van de Veerdonk began connecting the dots. In April, he and his group hypothesized that a dysregulated bradykinin system was leading to leaky blood vessels in the lungs and perhaps causing excess fluid to build up.
Josef Penninger, director of the Life Sciences Institute at the University of British Columbia in Vancouver who discovered that ACE2 is the essential in vivo receptor for SARS, tells The Scientist that he is convinced that bradykinin plays a role in COVID-19 pathogenesis. “It does make a lot of sense.”
He adds that Jacobson’s study lends support to the hypothesis, but further confirmation is needed. “Gene expression signatures don’t tell us the whole story. I think it is very important to actually measure the proteins.”
van de Veerdonk recognizes that peptide levels need to be measured and is currently setting up mass spectrometry to measure kinins in the plasma, which have a half-life in plasma of just a few seconds.
In the meantime, Jacobson and his coauthors advocate in their paper for targeting the bradykinin pathway to counter the excess fluid present in the lungs of COVID-19 patients. As there are already a couple of approved drugs that can interfere with the kinin pathway, doctors have begun deploying them in a number of clinical trials.
Decoding the bradykinin inflammatory pathway in COVID-19
A common theme that underpins many of the disease manifestations of COVID-19, such as acute respiratory distress syndrome (ARDS), is inflammation and edema, or fluid build-up. An assorted cast of leaky blood vessels, immune cells (as well as the cytokines and other molecules produced by them), and plasma proteins such as clotting factors, bradykinin, and other kinins assume center stage in this spectacle of acute inflammation.
Activation of the kinin system in the context of blood clotting—which can be dysregulated in some COVID-19 patients—generates bradykinin and related peptides through two distinct pathways: the plasma kallikrein pathway (activated by a clotting factor called the Hageman factor) and the tissue kallikrein pathway (activated by tissue enzymes and plasmin, an enzyme in the fibrinolytic system that breaks down clots in the bloodstream). Bradykinin is then converted to des-Arg9-bradykinin (DABK). When bradykinin and DABK bind to their corresponding receptors, B 2 R and B 1 R, respectively, fluid begins to leak from blood vessels.
The leaky blood vessels and lung fluid build-up in some COVID-19 patients might be explained by the virus’s corruption of an inflammation safeguard, namely, ACE2’s degradation of DABK. Read the full description of the pathway here the scientist staff
The RAS pathway tightly controls the kinin system. ACE breaks down bradykinin, while ACE2 breaks down DABK. ACE and ACE2 therefore act as regulatory brakes in the kinin system. But because ACE2 combines with SARS and SARS-CoV-2 and is internalized into the cell during infection, extracellular levels of the enzyme might drop, and, according to van de Veerdonk’s hypothesis, the bradykinin cascade then goes into overdrive.
“As part of the explanation of COVID pathophysiology, it makes perfect sense, but it’s one piece of a very large and complex puzzle and it only partly helps us explain and understand better a very difficult disease,” says David Fedson, a retired general internist who is interested in developing treatments for pathogens that cause pandemics. Now it’s up to physicians to connect the dots and ask, “how is that meaningful and what can I do about it?—which is the most important question.”
Penninger, who is the founder of a company that is testing ACE2 as a treatment for lung failure in a Phase 2 trial in COVID-19 patients, agrees.
Targeting the bradykinin pathway in COVID
Currently, there are two approved drugs that target the kinin system: icatibant (a B 2 R blocker) and the monoclonal antibody lanadelumab, which inhibits plasma kallikrein (there are no drugs yet approved that inhibit tissue kallikrein). van de Veerdonk contends that targeting the kinin system early in the disease, soon after a patient is hospitalized, and is hypoxic, but hasn’t yet developed ARDS, might be helpful.
That is what his group found in a small exploratory study published this month. COVID-19 patients taking icatibant showed marked improvement in oxygenation as evidenced by a substantial decrease in need for supplemental oxygen, compared to control patients.
Allen Kaplan, a professor at the Medical University of South Carolina and an expert on bradykinin who was not connected with the study, tells The Scientist that this preliminary observation supports the idea that icatibant might be helpful “and should therefore be studied in a double-blind placebo-controlled fashion [in COVID patients].”
Another multicenter randomized clinical trial in the US is testing icatibant in critically ill COVID-19 patients in the ICU.
A clinical trial in Cleveland is testing lanadelumab in COVID-19 patients with pneumonia.
van de Veerdonk’s group is also testing the plasma kallikrein inhibitor (which is being supplied by Takeda, a company that also manufactures icatibant) in a multicenter clinical trial in the Netherlands in hospitalized COVID-19 patients receiving supplemental oxygen, to see whether the drug decreases the need for oxygen.
If all goes well for van de Veerdonk and his team, lanadelumab will be integrated into the REMAP-CAP trial that is evaluating several drugs for community-acquired pneumonia in thousands of patients across several countries and includes COVID-19 patients in one arm.
Kaplan has his reservations, and notes that using the monoclonal antibody against plasma kallikrein in COVID-19 could be interesting, but if it turns out that tissue kallikrein is more important in the disease, it won’t work.
Clarification (August 27): The seventh paragraph initially indicated that van de Veerdonk is currently using mass spectrometry to measure kallikreins in the plasma of COVID-19 patients and that it was impossible to do the same for bradykinin, which has a half-life in plasma of just a few seconds. This has now been changed to clarify that van de Veerdonk is currently setting up mass spectrometry to measure kinins in the plasma, which have a very short half-life.


thescientist--2020-08-26--Infographic: SARS-CoV-2 Interferes with Bradykinin Regulation

Interplay between the kinin pathway , which mediates acute inflammation ; the renin-angiotensin system ( RAS ) , which regulates @ @ @ @ @ ; and macrophages , immune cells that are activated in infection , leads to leaky @ @ @ @ @ some cases of SARS-CoV-2 infection .
Researchers propose that the kinin cascade—in which bradykinin and @ @ @ @ @ major proteins—goes into overdrive to cause these effects during COVID-19 .
Ordinarily , the RAS—in @ @ @ @ @ ) and ACE2 are key enzymes—keeps the kinin cascade under control .
ACE breaks down @ @ @ @ @ it from binding to its receptor B R , while ACE2 degrades DABK and stops @ @ @ @ @ R. When SARS-CoV-2 hooks up with ACE2 as a means of entering cells , some @ @ @ @ @ , according to the model , thereby permitting DABK to bind to its receptor and @ @ @ @ @ inflammation .
Activated macrophages secrete proinflammatory cytokines such as interleukin-1 and tumor necrosis factor-alpha , @ @ @ @ @ R to amplify the inflammatory milieu seen in COVID-19 .

the scientist staff
Interplay between the kinin pathway, which mediates acute inflammation; the renin-angiotensin system (RAS), which regulates blood pressure and fluid balance; and macrophages, immune cells that are activated in infection, leads to leaky blood vessels and inflammation in some cases of SARS-CoV-2 infection.
Researchers propose that the kinin cascade—in which bradykinin and des-Arg9-bradykinin (DABK) are major proteins—goes into overdrive to cause these effects during COVID-19. Ordinarily, the RAS—in which angiotensin-converting enzyme (ACE) and ACE2 are key enzymes—keeps the kinin cascade under control. ACE breaks down the protein bradykinin, preventing it from binding to its receptor B 2 R, while ACE2 degrades DABK and stops it from binding to B 1 R. When SARS-CoV-2 hooks up with ACE2 as a means of entering cells, some of the brakes are removed, according to the model, thereby permitting DABK to bind to its receptor and trigger blood vessel leakage and inflammation.
Activated macrophages secrete proinflammatory cytokines such as interleukin-1 and tumor necrosis factor-alpha, which in turn induce B 1 R to amplify the inflammatory milieu seen in COVID-19.
Read the full story, “Is a Bradykinin Storm Brewing in COVID-19?”


thescientist--2020-08-26--Mastering Cell Imaging Assays

Mastering Cell Imaging Assays

Live cell imaging is one of the most important techniques used in life sciences today .
Researchers increasingly need physiologically @ @ @ @ @ cell-based assays , but these complex and advanced techniques place great demands on the detection @ @ @ @ @ .
A new automated cell imaging technology eases the strain .
Download this ebook from @ @ @ @ @ Cell analysis is automated at the bench

Using cell imaging, scientists determine basic structural properties and visualize changes in morphology and behavior post-treatment. Cell imaging instruments can visualize, image, quantify, and analyze cells, yielding information in real-time and offering data on both single-cell and population dynamics. Data acquired using robust instrumentation can positively impact the success and reproducibility of downstream assays.
Download this ebook from Tecan to review key factors when choosing cell imaging technology and examine how cell imaging technology can aid various cell-based assays and applications.


thescientist--2020-08-26--Thousands of Coronavirus Infections Stemmed from a Biotech Event

In February of this year , more than 100 leaders of the drug company Biogen met in Boston .
Among them was at least one person infected with COVID-19 .
While the Massachusetts Department of Public Health initially identified 97 cases linked to the conference through contact tracing , a new study detailing the genomes of viruses collected from the Greater Boston area indicates that the gathering may have led to more than 20,000 cases across four counties .
The authors of the study arrived at the new count using what Bronwyn MacInnis , an infectious disease researcher at the @ @ @ @ @ @ @ the paper , describes to the Associated Press as “ a pretty unsophisticated , back-of-the envelope calculation.
” The total does not appear in the paper , posted August 25 on the preprint server medRxiv , but her coauthor Jacob Lemieux , an infectious disease physician at Massachusetts General Hospital , tells the Boston Globe , “ I ’ m confident that the scale for measuring this event is in the tens of thousands.
” In late February , when the conference began , Vice President Mike Pence was just forming his coronavirus @ @ @ @ @ @ @ dozen COVID-19 cases identified in the US , and the authors stress that they are not faulting Biogen .
In a prepared statement sent to The Washington Post , Biogen shared that they had followed all necessary precautions available at the time and immediately reported each case to health officials .
Shortly after people began falling ill , employees at Biogen realized they had an opportunity to “ offer their own anonymized medical information to research efforts , ” Maha Radhakrishnan , the chief medical officer at Biogen , told The Scientist in @ @ @ @ @ @ @ realized we were in a unique position to contribute to advancing COVID-19 science in an organized and deliberate way.
” Their medical information became part of one of the most comprehensive viral genome studies to emerge out of the pandemic .
The research team , which included more than 50 scientists and public health officials from around Massachusetts , analyzed the genomes of SARS-CoV-2 pulled from 772 patients .
Almost all were from Essex , Middlesex , Norfolk , and Suffolk counties in Massachusetts who had visited a hospital or clinic between January @ @ @ @ @ @ @ including 28 people identified in the initial 97 cases linked to the conference .
See “ Biogen Uses its Own Superspreader Event to Aid COVID-19 Research ” As a virus replicates , it accumulates small , often insignificant changes to its genetic code .
Scientists identified a single mutation common in the virus of those who attended the conference , a mutation they named C2416T for its location along the genome and the two nucleic acids , cytosine ( C ) and uracil ( the T is for thymine , which replaces RNA @ @ @ @ @ @ @ that were switched .
The authors found this mutation in 289 patients—more than one-third of all the people they looked at—far outstripping the number of people who had attended the conference .
In fact , those 289 genomes represent 3 percent of all the SARS-CoV-2 genomes sequenced in the entire United States , according to the Post .
A large percentage of these cases stemmed from local homeless individuals taking refuge in shelters and the employees who worked there , a finding that Pardis Sabeti , a computational biologist at the Broad Institute @ @ @ @ @ @ @ the study , calls jaw-dropping .
“ It was the realization that these events really affect the most vulnerable among us , ” Sabeti tells The Post .
It ’ s unknown how the virus jumped from the conference to those living on the streets of Boston .
The researchers also identified another 79 unique variants of SARS-CoV-2 that had been introduced into Boston , mostly from other US states or from western Europe , the authors report .
And just as variants pour into an area , so they spread outward .
@ @ @ @ @ @ @ the molecular signature of the Biogen outbreak has been found in patients in Tennessee , North Carolina , Indiana , New Jersey , Washington , DC , and overseas , according to the Globe .
“ This is the kind of study that .
.
.
defines why genomics can be so useful in outbreak reconstruction , ” Vaughn Cooper , a microbiologist at the University of Pittsburgh who was not involved in the study , tells the Globe .
“ It reflects a great deal of coordinating work , and that ’ @ @ @ @ @ @ @ powerful . ''
Outside experts have also largely accepted the team ’ s estimation of how many cases may be attributable to the conference .
Caroline Buckee , an epidemiologist at Harvard University , tells the Globe she has no problem believing a single event could cause 20,000 cases .
“ Super-spreading is really a key component of how we ended up with an epidemic of this gravity , ” she says .
Similarly , Dan Hartl , a population geneticist at Harvard University who was not involved in the study , tells @ @ @ @ @ @ @ of 20,000 cases credible , “ although I grant you it ’ s eye-popping.
” The authors have been quick to urge that there is nothing particularly special about the C2416T variant that makes it more powerful than other strains .
“ Some [ viral ] introductions fizzle out , others light fires , ” MacInnis tells the Globe .
“ The circumstances of this event ?
the fact that it happened so early in the epidemic and the timing of where we were with COVID in the public consciousness ?
meant it @ @ @ @ @ @

ABOVE: © ISTOCK.COM, JUSUN
In February of this year, more than 100 leaders of the drug company Biogen met in Boston. Among them was at least one person infected with COVID-19.
While the Massachusetts Department of Public Health initially identified 97 cases linked to the conference through contact tracing, a new study detailing the genomes of viruses collected from the Greater Boston area indicates that the gathering may have led to more than 20,000 cases across four counties.
The authors of the study arrived at the new count using what Bronwyn MacInnis, an infectious disease researcher at the Broad Institute and the senior author of the paper, describes to the Associated Press as “a pretty unsophisticated, back-of-the envelope calculation.” The total does not appear in the paper, posted August 25 on the preprint server medRxiv, but her coauthor Jacob Lemieux, an infectious disease physician at Massachusetts General Hospital, tells the Boston Globe, “I’m confident that the scale for measuring this event is in the tens of thousands.”
In late February, when the conference began, Vice President Mike Pence was just forming his coronavirus task force, there were a few dozen COVID-19 cases identified in the US, and the authors stress that they are not faulting Biogen. In a prepared statement sent to The Washington Post, Biogen shared that they had followed all necessary precautions available at the time and immediately reported each case to health officials.
Shortly after people began falling ill, employees at Biogen realized they had an opportunity to “offer their own anonymized medical information to research efforts,” Maha Radhakrishnan, the chief medical officer at Biogen, told The Scientist in an email in May. “We realized we were in a unique position to contribute to advancing COVID-19 science in an organized and deliberate way.”
Their medical information became part of one of the most comprehensive viral genome studies to emerge out of the pandemic. The research team, which included more than 50 scientists and public health officials from around Massachusetts, analyzed the genomes of SARS-CoV-2 pulled from 772 patients. Almost all were from Essex, Middlesex, Norfolk, and Suffolk counties in Massachusetts who had visited a hospital or clinic between January and May, the Globe reports, including 28 people identified in the initial 97 cases linked to the conference.
As a virus replicates, it accumulates small, often insignificant changes to its genetic code. Scientists identified a single mutation common in the virus of those who attended the conference, a mutation they named C2416T for its location along the genome and the two nucleic acids, cytosine (C) and uracil (the T is for thymine, which replaces RNA’s uracil in DNA), that were switched.
The authors found this mutation in 289 patients—more than one-third of all the people they looked at—far outstripping the number of people who had attended the conference. In fact, those 289 genomes represent 3 percent of all the SARS-CoV-2 genomes sequenced in the entire United States, according to the Post.
A large percentage of these cases stemmed from local homeless individuals taking refuge in shelters and the employees who worked there, a finding that Pardis Sabeti, a computational biologist at the Broad Institute and one of the lead researchers on the study, calls jaw-dropping. “It was the realization that these events really affect the most vulnerable among us,” Sabeti tells The Post. It’s unknown how the virus jumped from the conference to those living on the streets of Boston.
The researchers also identified another 79 unique variants of SARS-CoV-2 that had been introduced into Boston, mostly from other US states or from western Europe, the authors report. And just as variants pour into an area, so they spread outward. In addition to the local cases, the molecular signature of the Biogen outbreak has been found in patients in Tennessee, North Carolina, Indiana, New Jersey, Washington, DC, and overseas, according to the Globe.
“This is the kind of study that . . . defines why genomics can be so useful in outbreak reconstruction,” Vaughn Cooper, a microbiologist at the University of Pittsburgh who was not involved in the study, tells the Globe. “It reflects a great deal of coordinating work, and that’s what in part makes this so powerful."
Outside experts have also largely accepted the team’s estimation of how many cases may be attributable to the conference. Caroline Buckee, an epidemiologist at Harvard University, tells the Globe she has no problem believing a single event could cause 20,000 cases. “Super-spreading is really a key component of how we ended up with an epidemic of this gravity,” she says.
Similarly, Dan Hartl, a population geneticist at Harvard University who was not involved in the study, tells the Globe that he found the estimate of 20,000 cases credible, “although I grant you it’s eye-popping.”
The authors have been quick to urge that there is nothing particularly special about the C2416T variant that makes it more powerful than other strains. “Some [viral] introductions fizzle out, others light fires,” MacInnis tells the Globe. “The circumstances of this event?the fact that it happened so early in the epidemic and the timing of where we were with COVID in the public consciousness?meant it had a disproportionate effect.”


thescientist--2020-08-26--Campuses, Labs Close in Advance of Hurricane Laura

ABOVE : Floodwaters rise at the Louisiana Universities Marine Consortium in Chauvin , Louisiana , August 26 .
LOUISIANA UNIVERSITIES MARINE CONSORTIUM ( LUMCON ) Update ( August 27 ) : The subheading of this story has been updated to reflect the strength of the storm and when it made landfall .
As of this morning ( August 26 ) , the Louisiana Universities Marine Consortium , a field station on the Gulf Coast , was already flooded with two feet of water .
“ We anticipate several feet more ” as Hurricane Laura heads toward Louisiana this evening , @ @ @ @ @ @ @ Craig McClain , in an email to The Scientist .
This morning , the National Hurricane Center predicted the storm , currently a category 3 , will become “ an extremely dangerous category 4 hurricane.
” The staff at Louisiana Universities Marine Consortium ( LUMCON ) have been working to button up the labs since last week to guard against both Tropical Storm Marco , which brought heavy rains to the Gulf Coast this week , and Laura , close on its heels .
All of the center ’ s operations are shut @ @ @ @ @ @ @ .
McClain stresses that LUMCON was built to handle hurricanes , with elevated buildings and detailed safety plans—not to mention experience with past storms .
“ During Barry , we received almost 6 feet of water , ” McClain says of the 2019 storm that dumped up to 23 inches of rain in Louisiana .
“ We began cleanup on Monday , including several inches of deposited mud , and by Wednesday morning were operational again.
” Numerous other campuses have closed in anticipation of the hurricane .
Texas A & M University @ @ @ @ @ @ @ Tuesday and bussed students to College Station , while the University of Texas Medical Branch in Galveston likewise closed for nonessential duties .
According to an alert on its website yesterday , research labs are closed and specimens are being moved or secured .
Lamar University in Beaumont , Texas , is also under evacuation orders and the campus is shuttered for the week .
The University of Louisiana Lafayette closed campus and asked residents to shelter in place while Louisiana State University Shreveport is closing campus on Thursday as the hurricane is @ @ @ @ @ @ @ .
The University of Houston moved all classes online for the week and is limiting access to the campus today and tomorrow .
See “ Biology Labs Hit by Harvey ’ s Eye Face Long Road to Recovery ”

ABOVE: Floodwaters rise at the Louisiana Universities Marine Consortium in Chauvin, Louisiana, August 26.
LOUISIANA UNIVERSITIES MARINE CONSORTIUM (LUMCON)
Update (August 27): The subheading of this story has been updated to reflect the strength of the storm and when it made landfall.
As of this morning (August 26), the Louisiana Universities Marine Consortium, a field station on the Gulf Coast, was already flooded with two feet of water. “We anticipate several feet more” as Hurricane Laura heads toward Louisiana this evening, says the facility’s director, Craig McClain, in an email to The Scientist.
This morning, the National Hurricane Center predicted the storm, currently a category 3, will become “an extremely dangerous category 4 hurricane.”
The staff at Louisiana Universities Marine Consortium (LUMCON) have been working to button up the labs since last week to guard against both Tropical Storm Marco, which brought heavy rains to the Gulf Coast this week, and Laura, close on its heels. All of the center’s operations are shut down for the rest of the week.
McClain stresses that LUMCON was built to handle hurricanes, with elevated buildings and detailed safety plans—not to mention experience with past storms. “During Barry, we received almost 6 feet of water,” McClain says of the 2019 storm that dumped up to 23 inches of rain in Louisiana. “We began cleanup on Monday, including several inches of deposited mud, and by Wednesday morning were operational again.”
Numerous other campuses have closed in anticipation of the hurricane. Texas A&M University Galveston Campus issued a mandatory evacuation on Tuesday and bussed students to College Station, while the University of Texas Medical Branch in Galveston likewise closed for nonessential duties. According to an alert on its website yesterday, research labs are closed and specimens are being moved or secured. Lamar University in Beaumont, Texas, is also under evacuation orders and the campus is shuttered for the week.
The University of Louisiana Lafayette closed campus and asked residents to shelter in place while Louisiana State University Shreveport is closing campus on Thursday as the hurricane is expected to move northward through the state. The University of Houston moved all classes online for the week and is limiting access to the campus today and tomorrow.


thescientist--2020-08-26--The Scientist Speaks Podcast - Episode 8

In this month 's episode , Experimental Cures for Fragile Patients : Prenatal Stem Cell and Gene Therapies , brought @ @ @ @ @ and sponsored by NanoTemper Technologies , we discuss how scientists develop stem cell and gene @ @ @ @ @ in utero .
Niki Spahich from The Scientist ’ s Creative Services team spoke with @ @ @ @ @ a neonatologist at Boston Children ’ s Hospital , and Tippi MacKenzie , a Professor @ @ @ @ @ of San Francisco Medical School , to learn more .
The Scientist Speaks is a @ @ @ @ @ ’ s Creative Services team .
Our podcast is by scientists and for scientists .
@ @ @ @ @ will bring you the stories behind news-worthy molecular biology research .

For a long time, scientists have searched for cures for genetic diseases. As stem cell and gene therapies proved to be viable therapeutic options, researchers turned to prenatal applications to see if they could develop ways to bring fetuses with life-threatening conditions to term. Niki Spahich from The Scientist’s Creative Services team spoke with Amy O’Connell, a neonatologist at Boston Children’s Hospital, and Tippi MacKenzie, a Professor of Surgery at the University of San Francisco Medical School, to learn more.


thescientist--2020-08-26--Technology that Tracks, Shares, and Protects your Data – TRACKMAN® Connected

With TRACKMAN® Connected , researchers can track their pipetting steps , conveniently share their work with collaborators , and securely @ @ @ @ @ more at www.gilson.com/gilson-connect

With TRACKMAN® Connected, researchers can track their pipetting steps, conveniently share their work with collaborators, and securely protect their data. Learn more at www.gilson.com/gilson-connect


thescientist--2020-08-25--Patients Reinfected with Coronavirus in Hong Kong, Europe

Doctors have reported the first confirmed cases of individuals who have tested positive for SARS-CoV-2 infection a second time .
The first report was of a patient in Hong Kong , followed by two patients from Europe , Reuters reports .
Toward the end of March , a 33-year-old Hong Kong man came down with COVID-19 and experienced mild symptoms before his full recovery a couple of weeks later , The Washington Post reports .
After traveling to Spain over the summer , he tested positive in mid-August upon returning to Hong Kong .
Although he was asymptomatic , he @ @ @ @ @ @ @ showed that he became reinfected with a different strain of the novel coronavirus than the first time .
Two Europeans , one from Belgium and one from the Netherlands , are also reported to have been reinfected .
The Belgian woman first tested positive in March and again in June , while not much information about the Dutch patient is known , other than the individual is older and immunocompromised .
Some experts have told news outlets that they were not surprised by patients experiencing repeated infections , especially because the illness was @ @ @ @ @ @ @ and many are wondering what this means for the efficacy of a COVID-19 vaccine .
“ What we are learning from this new case report is that SARS-CoV-2 may persist in the global population , similar to other common cold-associated human coronaviruses , even if patients have some degree of acquired immunity , ” Robert Glatter , an ER doctor in New York City , says to the Post in reference to the Hong Kong patient .
While the patient ’ s immune response likely prevented him from getting sick the second time @ @ @ @ @ @ @ same would occur with a future vaccine .
Glatter notes that , like exposure to other coronaviruses , a vaccine “ may not be able to provide lifelong immunity , ” and might require booster shots .
A study on the Hong Kong patient has been accepted for publication in Clinical Infectious Diseases .
It is not clear if those who test positive a second time are capable of shedding the virus and affecting others .
According to Johns Hopkins University , there have been more than 23.5 million confirmed COVID-19 cases across @ @ @ @ @ @ @ clear how many cases of asymptomatic reinfection have occurred .
“ This might happen more often than we think , ” Mark Slifka , an immunologist at Oregon Health and Science University in Portland , tells Science News .
“ But no one ’ s swabbing people on a routine basis when they ’ re healthy .
”

ABOVE: © ISTOCK.COM, BODNARCHUCK
Doctors have reported the first confirmed cases of individuals who have tested positive for SARS-CoV-2 infection a second time. The first report was of a patient in Hong Kong, followed by two patients from Europe, Reuters reports.
Toward the end of March, a 33-year-old Hong Kong man came down with COVID-19 and experienced mild symptoms before his full recovery a couple of weeks later, The Washington Post reports. After traveling to Spain over the summer, he tested positive in mid-August upon returning to Hong Kong. Although he was asymptomatic, he quarantined in the hospital. Genetic testing showed that he became reinfected with a different strain of the novel coronavirus than the first time.
Two Europeans, one from Belgium and one from the Netherlands, are also reported to have been reinfected. The Belgian woman first tested positive in March and again in June, while not much information about the Dutch patient is known, other than the individual is older and immunocompromised.
Some experts have told news outlets that they were not surprised by patients experiencing repeated infections, especially because the illness was not as severe the second time, and many are wondering what this means for the efficacy of a COVID-19 vaccine.
“What we are learning from this new case report is that SARS-CoV-2 may persist in the global population, similar to other common cold-associated human coronaviruses, even if patients have some degree of acquired immunity,” Robert Glatter, an ER doctor in New York City, says to the Post in reference to the Hong Kong patient.
While the patient’s immune response likely prevented him from getting sick the second time around, there is no guarantee the same would occur with a future vaccine. Glatter notes that, like exposure to other coronaviruses, a vaccine “may not be able to provide lifelong immunity,” and might require booster shots.
A study on the Hong Kong patient has been accepted for publication in Clinical Infectious Diseases. It is not clear if those who test positive a second time are capable of shedding the virus and affecting others.
According to Johns Hopkins University, there have been more than 23.5 million confirmed COVID-19 cases across the globe. It’s not clear how many cases of asymptomatic reinfection have occurred.
“This might happen more often than we think,” Mark Slifka, an immunologist at Oregon Health and Science University in Portland, tells Science News. “But no one’s swabbing people on a routine basis when they’re healthy.”


thescientist--2020-08-25--Some COVID-19 Patients Lack Key Structures for Antibody Creation

ABOVE : Post-mortem thoracic lymph nodes of a COVID-19 patient ( left ) lack clusters of Bcl-6–bearing T cells and B cells ( stained in yellow ) , which populate the germinal centers and are clearly visible in a healthy control patient who died of other causes ( right ) .
COVID-19 patient lymph nodes also show different distributions of CD3+ T cells ( pink ) and CD19+ T cells ( turquoise ) .
NAOKI KANEKO AND SHIV PILLAI , RAGON INSTITUTE OF MASSACHUSETTS GENERAL HOSPITAL , MIT AND HARVARD When our immune system encounters a new virus—say , SARS-CoV-2—for @ @ @ @ @ @ @ plasmablast B cells will release a first flush of antibodies that can stick to and even neutralize the virus .
But those first antibodies are short-lived , typically don ’ t stick very strongly , and the cells that produce them don ’ t last longer than a few weeks .
As reinforcement , the immune system has a program in place to create long-lived plasma cells that secrete even better , more–tightly binding antibodies .
This takes place in the germinal center , a transient , complex structure in the lymph nodes @ @ @ @ @ @ @ cells gather and undergo a process that ’ s best described as evolution on the fast track .
They rapidly proliferate while deliberately introducing random mutations to certain genes encoding antibodies , increasing the chances of producing a few clones that can squelch the virus .
A type of T cell picks and chooses progeny with promising antibodies , while killing the less useful ones or directing them back for improvement—a cycle of refinement and selection that culminates in the creation of long-lived , plasma B cells that can protect us against re-infection @ @ @ @ @ @ @ cells , which last for even longer .
Without germinal centers , the body can not make lasting antibody immunity to pathogens .
Some severely affected COVID-19 patients entirely lack those structures , according to a post-mortem analysis of lymph and spleen tissue published last week ( August 19 ) in Cell .
The authors posit this could be due to high levels of a certain cytokine , TNF-α , which impairs the differentiation of the follicular helper T cells that are required for these germinal center reactions .
Although it ’ s @ @ @ @ @ @ @ COVID-19 patients induce better germinal center responses , the findings help explain why antibody-based immunity to SARS-CoV-2 may be relatively short-lived .
The study “ suggests an explanation for a very big problem , ” says Ziv Shulman of the Weizmann Institute of Science in Israel who wasn ’ t involved in the study .
“ The strength is that it ’ s not a model—we ’ re looking at the real disease.
” As a group that has previously studied germinal centers and B cell development , it was only natural for @ @ @ @ @ @ @ of Massachusetts General Hospital , MIT , and Harvard and his colleagues to investigate the sites in COVID-19 patients where germinal centers would be expected to form .
They examined the thoracic lymph nodes and spleens of 11 COVID-19 patients who had died of severe infection between March and May this year at Brigham and Women ’ s Hospital in Boston .
Yet when they stained the tissue with different markers typical of germinal centers , they found no signs of the antibody-producing depots .
This was in contrast to thoracic lymph nodes @ @ @ @ @ @ @ of other causes .
All of the control patients had germinal centers , likely because of ongoing immunity to harmless pathogens they carried .
“ The thing you ’ d expect to see is loaded germinal centers , ” Pillai says of the COVID-19 patients .
But the absence of the structures wasn ’ t a complete surprise .
Since April , several studies have reported antibodies in COVID-19 patients that don ’ t show the characteristically heavy mutational signature one would expect if they had stemmed from a germinal center .
In @ @ @ @ @ @ @ who died during the original SARS outbreak in 2003 found that germinal centers were absent there as well , notes Pillai , who ’ s on the scientific advisory board of the Massachusetts-based antibody therapeutics company Abpro and soon-to-launch Delaware-based B cell engineering startup Pulsar Biopharma .
In their tissue analyses of COVID-19 patients , Pillai ’ s team also documented a striking reduction of a particular kind of B cell that typically populates the germinal centers and produces the marker Bcl-6 .
This was accompanied by a lack of Bcl-6–bearing follicular helper @ @ @ @ @ @ @ kick-starting the formation of the germinal center as well as selecting promising B cells there .
The team surmised that the cytokine TNF-α , which was in unusually high concentrations around the would-be location of the germinal center , could be blocking the differentiation of T cells into Bcl-6 follicular helper T cells , thereby preventing the formation of germinal centers .
In mouse models of malaria in which germinal center reactions are defective , it ’ s known that blocking the cytokine can restore functional germinal centers .
The immune systems of @ @ @ @ @ @ @ route to create antibodies .
The team found a preponderance of another type of B cell in the lymph nodes and spleens of COVID-19 patients , so-called double-negative B cells , which have been linked to autoimmunity and other pathological conditions .
These are capable of creating antibody-secreting cells , but not the kind needed for long-term antibody immunity , notes Ankur Singh , an immune engineer at Georgia Tech who wasn ’ t involved in the research .
“ It ’ s a very useful study in terms of understanding how the @ @ @ @ @ @ @ ” he adds .
To Shulman , the absence of germinal centers in COVID-19 patients who died—whose immune systems weren ’ t capable of mounting an effective immune response—isn ’ t surprising .
A key question is , “ can we learn something from that about patients who don ’ t die or even asymptomatic [ people ] .
.
.
about long-lasting immunity ?
” Pillai ’ s team also conducted an analysis of blood from 68 living COVID-19 patients , spanning moderately ill , severely ill , and recovered patients .
@ @ @ @ @ @ @ they found that the double-negative cells and other B cell subtypes that are typically generated outside the germinal center—including ones that were specific to SARS-CoV-2—were prominent across moderately and severely affected patients .
“ All of them had these weird cells , ” Pillai says .
Although not proof that the inability to form germinal centers is a widespread phenomenon in COVID-19 , Pillai says he suspects that could be possible , even in mild cases .
Most SARS-CoV-2 antibodies documented so far exhibit a very small degree of hypermutation , also among @ @ @ @ @ @ @ they didn ’ t arise from a germinal center .
If a failure to produce germinal centers is common , then so too would be re-infection with SARS-CoV-2 , and that could have implications for the ability to reach herd immunity through natural infection , the authors suggest .
However , it wouldn ’ t have any bearing on a vaccine , because vaccination typically generates good germinal centers , Pillai says .
COVID-19 is a continuum of severity and symptoms , Singh says , and one would expect something like germinal center @ @ @ @ @ @ @ as well .
“ It ’ s quite possible that patients that have less severe disease may induce better germinal center reactions.
” In addition , some research has found a few mutated antibodies among the predominantly unmutated ones in people who have recovered from COVID-19 , which means that “ germinal center activity must take place to some extent , ” Shulman adds .
Both Singh and Shulman say they would like to see more research on the underlying mechanisms .
It ’ s not clear , for instance , why TNF-α—one @ @ @ @ @ @ @ this effect , and whether it ’ s the only cause of absent germinal centers .
“ I think that conclusion can not be made from this particular study , ” Singh says .
It ’ s also very hard to disentangle whether it ’ s a defect in the follicular T helper cells , or a B cell defect , that impairs the germinal center response , Shulman adds .
“ It ’ s very hard to say because the cells depend on one another.
” Other mechanisms are possible , Shulman @ @ @ @ @ @ @ COVID-19 patients , although they don ’ t stem from the germinal center , are relatively high-affinity antibodies and are often capable of neutralizing the virus .
It ’ s feasible that because the initial antibodies are good enough , the immune system doesn ’ t proceed with germinal center reactions , and makes do with antibodies that don ’ t provide long-lasting protection .
Figuring out how the germinal center is disrupted is something that requires animal studies , Shulman notes .
To that end , Pillai is currently trying to model @ @ @ @ @ @ @ questions .
As for the question of long-term immunity , he says , “ time will tell .
We have to follow patients up for a while , and that ’ s what we ’ ll do.
” N. Kaneko et al.
, “ Loss of Bcl-6-expressing T follicular helper cells and germinal centers in COVID-19 , ” Cell , doi:10.1016/j.cell.2020.08/025

ABOVE: Post-mortem thoracic lymph nodes of a COVID-19 patient (left) lack clusters of Bcl-6–bearing T cells and B cells (stained in yellow), which populate the germinal centers and are clearly visible in a healthy control patient who died of other causes (right). COVID-19 patient lymph nodes also show different distributions of CD3+ T cells (pink) and CD19+ T cells (turquoise).
NAOKI KANEKO AND SHIV PILLAI, RAGON INSTITUTE OF MASSACHUSETTS GENERAL HOSPITAL, MIT AND HARVARD
When our immune system encounters a new virus—say, SARS-CoV-2—for the first time, some of our plasmablast B cells will release a first flush of antibodies that can stick to and even neutralize the virus. But those first antibodies are short-lived, typically don’t stick very strongly, and the cells that produce them don’t last longer than a few weeks.
As reinforcement, the immune system has a program in place to create long-lived plasma cells that secrete even better, more–tightly binding antibodies. This takes place in the germinal center, a transient, complex structure in the lymph nodes and spleen. There, different B cells gather and undergo a process that’s best described as evolution on the fast track. They rapidly proliferate while deliberately introducing random mutations to certain genes encoding antibodies, increasing the chances of producing a few clones that can squelch the virus.
A type of T cell picks and chooses progeny with promising antibodies, while killing the less useful ones or directing them back for improvement—a cycle of refinement and selection that culminates in the creation of long-lived, plasma B cells that can protect us against re-infection for years, and also memory B cells, which last for even longer. Without germinal centers, the body cannot make lasting antibody immunity to pathogens.
Some severely affected COVID-19 patients entirely lack those structures, according to a post-mortem analysis of lymph and spleen tissue published last week (August 19) in Cell. The authors posit this could be due to high levels of a certain cytokine, TNF-α, which impairs the differentiation of the follicular helper T cells that are required for these germinal center reactions. Although it’s still unclear if asymptomatic or mildly affected COVID-19 patients induce better germinal center responses, the findings help explain why antibody-based immunity to SARS-CoV-2 may be relatively short-lived.
The study “suggests an explanation for a very big problem,” says Ziv Shulman of the Weizmann Institute of Science in Israel who wasn’t involved in the study. “The strength is that it’s not a model—we’re looking at the real disease.”
As a group that has previously studied germinal centers and B cell development, it was only natural for immunologist Shiv Pillai of the Ragon Institute of Massachusetts General Hospital, MIT, and Harvard and his colleagues to investigate the sites in COVID-19 patients where germinal centers would be expected to form. They examined the thoracic lymph nodes and spleens of 11 COVID-19 patients who had died of severe infection between March and May this year at Brigham and Women’s Hospital in Boston.
All of them had these weird cells. —Shiv Pillai, Ragon Institute
Yet when they stained the tissue with different markers typical of germinal centers, they found no signs of the antibody-producing depots. This was in contrast to thoracic lymph nodes and spleens from people who had died of other causes. All of the control patients had germinal centers, likely because of ongoing immunity to harmless pathogens they carried.
“The thing you’d expect to see is loaded germinal centers,” Pillai says of the COVID-19 patients. But the absence of the structures wasn’t a complete surprise. Since April, several studies have reported antibodies in COVID-19 patients that don’t show the characteristically heavy mutational signature one would expect if they had stemmed from a germinal center. In addition, some autopsy reports of patients who died during the original SARS outbreak in 2003 found that germinal centers were absent there as well, notes Pillai, who’s on the scientific advisory board of the Massachusetts-based antibody therapeutics company Abpro and soon-to-launch Delaware-based B cell engineering startup Pulsar Biopharma.
In their tissue analyses of COVID-19 patients, Pillai’s team also documented a striking reduction of a particular kind of B cell that typically populates the germinal centers and produces the marker Bcl-6. This was accompanied by a lack of Bcl-6–bearing follicular helper T cells, which are important for kick-starting the formation of the germinal center as well as selecting promising B cells there. The team surmised that the cytokine TNF-α, which was in unusually high concentrations around the would-be location of the germinal center, could be blocking the differentiation of T cells into Bcl-6 follicular helper T cells, thereby preventing the formation of germinal centers. In mouse models of malaria in which germinal center reactions are defective, it’s known that blocking the cytokine can restore functional germinal centers.
The immune systems of these patients may be taking an alternate route to create antibodies. The team found a preponderance of another type of B cell in the lymph nodes and spleens of COVID-19 patients, so-called double-negative B cells, which have been linked to autoimmunity and other pathological conditions. These are capable of creating antibody-secreting cells, but not the kind needed for long-term antibody immunity, notes Ankur Singh, an immune engineer at Georgia Tech who wasn’t involved in the research. “It’s a very useful study in terms of understanding how the virus is impacting critically ill people,” he adds.
To Shulman, the absence of germinal centers in COVID-19 patients who died—whose immune systems weren’t capable of mounting an effective immune response—isn’t surprising. A key question is, “can we learn something from that about patients who don’t die or even asymptomatic [people] . . . about long-lasting immunity?”
Pillai’s team also conducted an analysis of blood from 68 living COVID-19 patients, spanning moderately ill, severely ill, and recovered patients. Upon analyzing the patients’ cells, they found that the double-negative cells and other B cell subtypes that are typically generated outside the germinal center—including ones that were specific to SARS-CoV-2—were prominent across moderately and severely affected patients. “All of them had these weird cells,” Pillai says.
Although not proof that the inability to form germinal centers is a widespread phenomenon in COVID-19, Pillai says he suspects that could be possible, even in mild cases. Most SARS-CoV-2 antibodies documented so far exhibit a very small degree of hypermutation, also among mild cases, which is suggestive that they didn’t arise from a germinal center. If a failure to produce germinal centers is common, then so too would be re-infection with SARS-CoV-2, and that could have implications for the ability to reach herd immunity through natural infection, the authors suggest. However, it wouldn’t have any bearing on a vaccine, because vaccination typically generates good germinal centers, Pillai says.
COVID-19 is a continuum of severity and symptoms, Singh says, and one would expect something like germinal center formation to fall somewhere on that spectrum as well. “It’s quite possible that patients that have less severe disease may induce better germinal center reactions.” In addition, some research has found a few mutated antibodies among the predominantly unmutated ones in people who have recovered from COVID-19, which means that “germinal center activity must take place to some extent,” Shulman adds.
Both Singh and Shulman say they would like to see more research on the underlying mechanisms. It’s not clear, for instance, why TNF-α—one of several cytokines elevated in COVID-19—might have this effect, and whether it’s the only cause of absent germinal centers. “I think that conclusion cannot be made from this particular study,” Singh says. It’s also very hard to disentangle whether it’s a defect in the follicular T helper cells, or a B cell defect, that impairs the germinal center response, Shulman adds. “It’s very hard to say because the cells depend on one another.”
Other mechanisms are possible, Shulman notes. The antibodies initially formed in COVID-19 patients, although they don’t stem from the germinal center, are relatively high-affinity antibodies and are often capable of neutralizing the virus. It’s feasible that because the initial antibodies are good enough, the immune system doesn’t proceed with germinal center reactions, and makes do with antibodies that don’t provide long-lasting protection. Figuring out how the germinal center is disrupted is something that requires animal studies, Shulman notes.
To that end, Pillai is currently trying to model mild COVID-19 in mice to investigate these questions. As for the question of long-term immunity, he says, “time will tell. We have to follow patients up for a while, and that’s what we’ll do.”
N. Kaneko et al., “Loss of Bcl-6-expressing T follicular helper cells and germinal centers in COVID-19,” Cell, doi:10.1016/j.cell.2020.08/025