Early Host Cell Targets of Yersinia pestis during Primary Pneumonic Plague

Abstract

Inhalation of Yersinia pestis causes primary pneumonic plague, a highly lethal syndrome with mortality rates approaching 100%. Pneumonic plague progression is biphasic, with an initial pre-inflammatory phase facilitating bacterial growth in the absence of host inflammation, followed by a pro-inflammatory phase marked by extensive neutrophil influx, an inflammatory cytokine storm, and severe tissue destruction. Using a FRET-based probe to quantitate injection of effector proteins by the Y. pestis type III secretion system, we show that these bacteria target alveolar macrophages early during infection of mice, followed by a switch in host cell preference to neutrophils. We also demonstrate that neutrophil influx is unable to limit bacterial growth in the lung and is ultimately responsible for the severe inflammation during the lethal pro-inflammatory phase. Inhalation of the bacterium Yersinia pestis results in primary pneumonic plague, a severe necrotizing pneumonia with mortality rates approaching 100% in the absence of timely antibiotic administration. Despite the notoriety of Y. pestis as a potential biological weapon and its well-established pandemic potential, very little is known regarding early host-pathogen interactions that lead to the progression of pulmonary infection. Y. pestis harbors a type III secretion system (T3SS) for delivery of Yersinia outer protein (Yop) effectors into host cells, an early and essential step in pathogenesis. In the work presented here, we identify the host cell targets of Y. pestis Yop secretion in the lung. We show that Y. pestis initially targets alveolar macrophages, followed by a shift in host cell preference to neutrophils. Through cellular depletion studies, we demonstrate that Y. pestis is highly resistant to macrophage- and neutrophil-mediated clearance, and that the accumulation of neutrophils in the lung is responsible for the severe necrotizing pneumonia that develops during the pro-inflammatory phase of pneumonic plague.