Inhibition of Neutrophil Primary Granule Release during Yersinia pestis Pulmonary Infection.

Inhalation of causes primary pneumonic plague, the most severe manifestation of plague that is characterized by a dramatic neutrophil influx to the lungs. Neutrophils are ineffective during primary pneumonic plague, failing to control growth in the airways. However, the mechanisms by which resists neutrophil killing are incompletely understood. Here, we show that inhibits neutrophil degranulation, an important line of host innate immune defense. We observed that neutrophils from the lungs of mice infected intranasally with fail to release primary granules throughout the course of disease. Using a type III secretion system (T3SS) injection reporter strain, we determined that directly inhibits neutrophil granule release by a T3SS-dependent mechanism. Combinatorial mutant analysis revealed that a strain lacking both effectors YopE and YopH did not inhibit primary granule release and is killed by neutrophils both and Similarly, strains injecting only YopE or YopH are able to inhibit the majority of primary granule release from human neutrophils. We determined that YopE and YopH block Rac2 activation and calcium flux, respectively, to inhibit neutrophil primary granule release in isolated human neutrophils. These results demonstrate that coordinates the inhibition of neutrophil primary granule release through the activities of two distinct effectors, and this inhibition promotes survival during primary pneumonic plague. is the causative agent of plague and is one of the deadliest human pathogens. The pneumonic form of infection has played a critical role in the severity of both historical and modern plague outbreaks, yet the host-pathogen interactions that govern the lethality of pulmonary infections are incompletely understood. Here, we report that inhibits neutrophil degranulation during infection, rendering neutrophils ineffective and allowing unrestricted growth of in the lungs. This coordinated inhibition of granule release not only demonstrates the pathogenic benefit of "silencing" lung neutrophils but also reveals specific host processes and pathways that could be manipulated to reduce the severity of primary pneumonic plague.