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.
Highlights
Acute bacterial pneumonia is the result of active colonization of the airspace in the lungs combined with host inflammation that is unable to resolve due to host-pathogen interactions as well as progressing host- and microbial- induced injury
Host-cell lysis was dependent on the T3SS, and only 5% lactate dehydrogenase (LDH) release was observed following infection of RAW macrophages with Y. pestis lacking the T3SS virulence plasmid pCD1
CCR2 is necessary for clearance of Y. pestis yopK We recently showed that C57BL/6 Ccr22/2 mice develop pneumonic plague with similar kinetics as wild type mice suggesting that CCR2+ cells may play only a minor role during WT infection [48]
Summary
Acute bacterial pneumonia is the result of active colonization of the airspace in the lungs combined with host inflammation that is unable to resolve due to host-pathogen interactions as well as progressing host- and microbial- induced injury. Alveolar and interstitial macrophages act as sentinel cells and react to pathogen-associated molecular patterns following bacterial invasion of the lung mucosa by activating pro-inflammatory cytokine production and phagocytosis. Activated alveolar macrophages retain a proinflammatory role and apoptosis of these macrophages signals the down-regulation of inflammation and induction of tissue repair. When efferocytosis by interstitial macrophages does not occur, increased severity of pneumonia results while, treatment of mice with apoptotic macrophages is protective against lethality [3,4]. Apoptosis provides both pro- and anti-inflammatory signals and each is necessary to prevent bacterial pneumonia
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