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.