title: Early apoptosis of macrophages modulated by injection of Yersinia pestis YopK promotes progression of primary pneumonic plague.
abstract: Yersinia pestis causes pneumonic plague, a disease characterized by inflammation, necrosis and rapid bacterial growth which together cause acute lung congestion and lethality. The bacterial type III secretion system (T3SS) injects 7 effector proteins into host cells and their combined activities are necessary to establish infection. Y. pestis infection of the lungs proceeds as a biphasic inflammatory response believed to be regulated through the control of apoptosis and pyroptosis by a single, well-conserved T3SS effector protein YopJ. Recently, YopJ-mediated pyroptosis, which proceeds via the NLRP3-inflammasome, was shown to be regulated by a second T3SS effector protein YopK in the related strain Y. pseudotuberculosis. In this work, we show that for Y. pestis, YopK appears to regulate YopJ-mediated apoptosis, rather than pyroptosis, of macrophages. Inhibition of caspase-8 blocked YopK-dependent apoptosis, suggesting the involvement of the extrinsic pathway, and appeared cell-type specific. However, in contrast to yopJ, deletion of yopK caused a large decrease in virulence in a mouse pneumonic plague model. YopK-dependent modulation of macrophage apoptosis was observed at 6 and 24 hours post-infection (HPI). When YopK was absent, decreased populations of macrophages and dendritic cells were seen in the lungs at 24 HPI and correlated with resolution rather than progression of inflammation. Together the data suggest that Y. pestis YopK may coordinate the inflammatory response during pneumonic plague through the regulation of apoptosis of immune cells.
authors: Department of Veterinary Pathobiology, University of Missouri, Columbia, Missouri, USA.
authors: Kristen N
authors: KN
authors: Peters
authors: Miqdad O
authors: MO
authors: Dhariwala
authors: Jennifer M
authors: JM
authors: Hughes Hanks
authors: Charles R
authors: CR
authors: Brown
authors: Deborah M
authors: DM
authors: Anderson
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D058947:Bacterial Secretion Systems; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D008264:Macrophages / Q000276:immunology* / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010930:Plague / Q000276:immunology*; D011401:Promoter Regions, Genetic; D015010:Yersinia pestis / Q000276:immunology* / Q000378:metabolism / Q000472:pathogenicity
chemical_list: D051017:Apoptosis Regulatory Proteins; D001426:Bacterial Proteins; D058947:Bacterial Secretion Systems; C109227:YopP protein, Yersinia; D053148:Caspase 3; D053181:Caspase 8
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