Inhalation of Yersinia pestis results in primary pneumonic plague, a highly 
lethal and rapidly progressing necrotizing pneumonia. The disease begins with a 
period of extensive bacterial replication in the absence of disease symptoms, 
followed by the sudden onset of inflammatory responses that ultimately prove 
fatal. Very little is known about the bacterial and host factors that contribute 
to the rapid biphasic progression of pneumonic plague. In this work, we analyzed 
the in vivo transcription kinetics of 288 bacterial open reading frames 
previously shown by microarray analysis to be dynamically regulated in the lung. 
Using this approach combined with bacterial genetics, we were able to identify 
five Y. pestis genes that contribute to the development of pneumonic plague. 
Deletion of one of these genes, ybtX, did not alter bacterial survival but 
attenuated host inflammatory responses during late-stage disease. Deletion of 
ybtX in another lethal respiratory pathogen, Klebsiella pneumoniae, also 
resulted in diminished host inflammation during infection. Thus, our in vivo 
transcriptional screen has identified an important inflammatory mediator that is 
common to two Gram-negative bacterial pathogens that cause severe pneumonia.
IMPORTANCE: Yersinia pestis is responsible for at least three major pandemics, 
most notably the Black Death of the Middle Ages. Due to its pandemic potential, 
ease of dissemination by aerosolization, and a history of its weaponization, 
Y. pestis is categorized by the Centers for Disease Control and Prevention as a 
tier 1 select agent most likely to be used as a biological weapon. To date, 
there is no licensed vaccine against Y. pestis. Importantly, an early "silent" 
phase followed by the rapid onset of nondescript influenza-like symptoms makes 
timely treatment of pneumonic plague difficult. A more detailed understanding of 
the bacterial and host factors that contribute to pathogenesis is essential to 
understanding the progression of pneumonic plague and developing or enhancing 
treatment options.