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.