The Pla Protease of Yersinia pestis Degrades Fas Ligand to Manipulate Host Cell Death and Inflammation

Pneumonic plague is a deadly respiratory disease caused by Yersinia pestis. The bacterial protease Pla contributes to disease progression and manipulation of host immunity, but the mechanisms by which this occurs are largely unknown. Here we show that Pla degrades the apoptotic signaling molecule Fas ligand (FasL) to prevent host cell apoptosis and inflammation. Wild-type Y. pestis, but not a Pla mutant (Δpla), degrades FasL, which results in decreased downstream caspase-3/7 activation and reduced apoptosis. Similarly, lungs of mice challenged with wild-type Y. pestis show reduced levels of FasL and activated caspase-3/7 compared to Δpla infection. Consistent with a role for FasL in regulating immune responses, Δpla infection results in aberrant proinflammatory cytokine levels. The loss of FasL or inhibition of caspase activity alters host inflammatory responses and enables enhanced Y. pestis outgrowth in the lungs. Thus, by degrading FasL, Y. pestis manipulates host cell death pathways to facilitate infection. [Display omitted] •FasL is a newly identified host substrate of the Pla protease of Y. pestis•FasL degradation prevents pulmonary caspase-3/7 activation and host cell apoptosis•Y. pestis manipulates innate immunity during pneumonic plague via FasL degradation•FasL degradation by Pla enables the full virulence of Y. pestis in the lungs The Yersinia pestis Pla protease is critical for the development of plague. Caulfield et al. identify the host signaling molecule Fas ligand as a Pla substrate. Y. pestis Pla degrades FasL to prevent the activation of host cell death pathways and innate inflammatory responses during infection.