Date Published: April 25, 2013
Publisher: Public Library of Science
Author(s): Kristen N. Peters, Miqdad O. Dhariwala, Jennifer M. Hughes Hanks, Charles R. Brown, Deborah M. Anderson, Ralph R. Isberg.
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.
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. Resident macrophages in the lungs play an important role in orchestrating the mucosal immune response and subsequent tissue repair following infection . 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. Following chemotaxis, neutrophils are the primary mediators of bacterial clearance. After neutrophils destroy invading extracellular bacteria, interstitial macrophages activate a resolution program, allowing efferocytosis and clearance of apoptotic neutrophils . Activated alveolar macrophages retain a pro-inflammatory 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, conversely, treatment of mice with apoptotic macrophages is protective against lethality , . Apoptosis provides both pro- and anti-inflammatory signals and each is necessary to prevent bacterial pneumonia.
The TNF receptor super family is a group of cell surface proteins including TNF-receptor and Fas that are involved in inducing programmed cell death to an extracellular ligand, the extrinsic apoptosis pathway . Yersinia infection has been shown to induce the assembly of the pro-caspase-8-containing death receptor complex, known as the DISC, independent of TNF or Fas receptor signaling, thereby activating caspase-8 (Figure 9) . YopJ is essential for activation of apoptosis due to its ability to shut down production of anti-apoptotic proteins and to stimulate assembly of an atypical DISC. YopK is located at the plasma membrane, associated with the translocation pore, where it could regulate, either directly or indirectly, YopJ activity in promoting DISC assembly or downstream signaling.