Pneumonic plague is a fatal disease caused by Yersinia pestis that is associated 
with a delayed immune response in the lungs. Because neutrophils are the first 
immune cells recruited to sites of infection, we investigated the mechanisms 
responsible for their delayed homing to the lung. During the first 24 hr after 
pulmonary infection with a fully virulent Y. pestis strain, no significant 
changes were observed in the lungs in the levels of neutrophils infiltrate, 
expression of adhesion molecules, or the expression of the major neutrophil 
chemoattractants keratinocyte cell-derived chemokine (KC), macrophage 
inflammatory protein 2 (MIP-2) and granulocyte colony stimulating factor 
(G-CSF). In contrast, early induction of chemokines, rapid neutrophil 
infiltration and a reduced bacterial burden were observed in the lungs of mice 
infected with an avirulent Y. pestis strain. In vitro infection of lung-derived 
cell-lines with a YopJ mutant revealed the involvement of YopJ in the inhibition 
of chemoattractants expression. However, the recruitment of neutrophils to the 
lungs of mice infected with the mutant was still delayed and associated with 
rapid bacterial propagation and mortality. Interestingly, whereas KC, MIP-2 and 
G-CSF mRNA levels in the lungs were up-regulated early after infection with the 
mutant, their protein levels remained constant, suggesting that Y. pestis may 
employ additional mechanisms to suppress early chemoattractants induction in the 
lung. It therefore seems that prevention of the early influx of neutrophils to 
the lungs is of major importance for Y. pestis virulence. Indeed, pulmonary 
instillation of KC and MIP-2 to G-CSF-treated mice infected with Y. pestis led 
to rapid homing of neutrophils to the lung followed by a reduction in bacterial 
counts at 24 hr post-infection and improved survival rates. These observations 
shed new light on the virulence mechanisms of Y. pestis during pneumonic plague, 
and have implications for the development of novel therapies against this 
pathogen.