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.
Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Adam J
AJ
Caulfield
Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Margaret E
ME
Walker
Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Lindsay M
LM
Gielda
Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. Electronic address: lathem@northwestern.edu.
Wyndham W
WW
Lathem
D000818:Animals; D017209:Apoptosis; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D053148:Caspase 3 / Q000096:biosynthesis*; D053179:Caspase 7 / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D018450:Disease Progression; D053222:Fas Ligand Protein / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007249:Inflammation; D019169:Jurkat Cells; D008168:Lung / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010930:Plague / Q000473:pathology; D010960:Plasminogen Activators / Q000235:genetics / Q000378:metabolism*; D015010:Yersinia pestis / Q000235:genetics / Q000472:pathogenicity*
D001426:Bacterial Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; C078140:Pla protease, Yersinia pestis; D010960:Plasminogen Activators; D053148:Caspase 3; D053179:Caspase 7