Circumventing <i>Y</i>. <i>pestis</i> Virulence by Early Recruitment of Neutrophils to the Lungs during Pneumonic Plague

<div><p>Pneumonic plague is a fatal disease caused by <i>Yersinia pestis</i> 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 <i>Y</i>. <i>pestis</i> 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 <i>Y</i>. <i>pestis</i> strain. <i>In vitro</i> 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 <i>Y</i>. <i>pestis</i> 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 <i>Y</i>. <i>pestis</i> virulence. Indeed, pulmonary instillation of KC and MIP-2 to G-CSF-treated mice infected with <i>Y</i>. <i>pestis</i> 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 <i>Y</i>. <i>pestis</i> during pneumonic plague, and have implications for the development of novel therapies against this pathogen.</p>