Research Article: Early Host Cell Targets of Yersinia pestis during Primary Pneumonic Plague

Date Published: October 3, 2013

Publisher: Public Library of Science

Author(s): Roger D. Pechous, Vijay Sivaraman, Paul A. Price, Nikolas M. Stasulli, William E. Goldman, Barbara I. Kazmierczak.


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.

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The historical impact of Yersinia pestis on humanity cannot be understated, as three major pandemics including the “Black Death” of the Middle Ages have been attributed to Y. pestis[1], [2]. The bacterium can be transmitted person-to-person via respiratory droplets resulting in primary pneumonic plague, which is the deadliest manifestation of Y. pestis infection [1], [2], [3]. In the event of respiratory exposure in humans, mortality rates are nearly 100% with a time to death of typically between four and seven days [1]. Its extreme lethality and history of weaponization have led to the assignment of Y. pestis as a Tier 1 Select Agent and compound fears of its intentional release as a weapon of bioterrorism [1].

The work presented here is the first to identify the initial host cell targets of fully virulent Y. pestis during pulmonary infection. Using flow cytometry to monitor injection of a YopE-TEM fusion protein by the T3SS, we showed that Y. pestis initially targets CD11chigh alveolar macrophages and neutrophils in the lung. Previously, Bosio et al. demonstrated that the attenuated (pgm- pCD1-) Y. pestis strain A1122 was taken up by a distinct CD11c+ CD11b− host population in the lungs following intratracheal inoculation, confirming that Y. pestis initially encounters alveolar macrophages early during infection [14]. By 12 hpi there is a dramatic shift in host target cell preference from macrophages to neutrophils that continues to increase by 24 hpi. This corresponds with a massive influx of neutrophils into the lung that is detected as early as 6 hpi. In addition to neutrophils, flow cytometry analysis of infected lungs revealed a 10-fold increase in numbers of CD11bhigh DCs by 24 hpi. CD11bhigh DCs are known to accumulate in airways adjacent to alveolar spaces after allergen challenge, and have been implicated in the events that define asthma as well as contributing to CD4+ T-cell priming [19], [20]. Infected lungs also saw an overall increase in levels of F4/80+CD11b+CD11c+ cells. These cells exhibited positivity for both interstitial (CD11b+) and alveolar (CD11c+) macrophage markers and were not targeted by clodrosome in uninfected mice. This population likely consists of a subset of dendritic cells expressing F4/80, activated alveolar macrophages expressing CD11b, and macrophages that have entered the lung in response to bacterial challenge and are induced to express CD11c [21]. Taken together, these results outline a highly dynamic lung environment early during infection where different host innate immune populations are expanding in the lung in an attempt to control Y. pestis infection, albeit without much success. Despite the expansion of these cell types, macrophages and neutrophils remained the primary targets of YopE injection.




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