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Project SummaryImmune defense against bacterial infection requires activation of conserved signaling pathways that upregulateproduction of inflammatory mediators to clear infection. Many pathogens, including the pathogenic Yersiniainhibit these signaling pathways in order to evade host immune defenses. Yersinia pseudotuberculosis (Yp)blocks NF-?B and MAPK signaling and interferes with inflammatory gene expression but also inducesapoptosis in innate immune cells. We recently demonstrated that YopJ-induced apoptosis itself is critical forhost defense against Yp infection. How apoptosis contributes to immune defense against pathogens that blockimmune signaling pathways, and how this apoptosis is regulated remains poorly understood. We haveidentified a novel regulator of apoptosis pathways, termed CARD19, which plays a key role in multiplepathways of caspase-dependent cell death. Notably, CARD19 deficiency results in increased susceptibility tooral infection by Y. pseudotuberculosis further supporting the role of cell death in response to Yersinia infectionas a key host immune protective mechanism. Our preliminary data demonstrate that CARD19 is localized tothe mitochondria, similarly to another mitochondrial CARD-containing protein, MAVS. Our central hypothesis isthat Yersinia infection promotes cell death via oligomerization of CARD19 and disruption of mitochondrialfunction. Moreover, we hypothesize that this cell death releases pro-inflammatory signals that alert uninfectedneighboring cells to the presence of infection. How CARD19-induced cell death is coupled to inflammatoryresponses and host defense against bacterial infection is not known. This pathway likely responds to manypathogens that block critical innate immune signaling pathways and in the context of pathological stimuli thatlead to CARD19-induced cell death. We propose two Specific Aims to address this important gap in ourknowledge. First we will define the molecular basis for CARD19-induced cell death. Second, we will determinethe contribution of CARD19 to downstream pathogen-specific immune responses and will dissect whetherCARD19 functions in a cell extrinsic manner via release of specific alarmins to mediate host immune defense.

Brodsky, Igor E
University of Pennsylvania
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