The Epithelial Transmembrane Protein PERP Is Required for Inflammatory Responses to S. typhimurium Infection: A Dissertation
Authors
Hallstrom, Kelly N.Faculty Advisor
Beth McCormick, PhDAcademic Program
Immunology and MicrobiologyUMass Chan Affiliations
Microbiology and Physiological SystemsDocument Type
Doctoral DissertationPublication Date
2015-10-28Keywords
Dissertations, UMMSBacterial Proteins
Caspase 3
Epithelial Cells
Inflammation
Membrane Proteins
Microfilament Proteins
Neutrophils
Salmonella Infections
Salmonella enterica
Salmonella typhimurium
Bacterial Proteins
Caspase 3
Epithelial Cells
Inflammation
Membrane Proteins
Microfilament Proteins
Neutrophils
Salmonella Infections
Salmonella enterica
Salmonella typhimurium
Bacterial Infections and Mycoses
Bacteriology
Immunology of Infectious Disease
Immunopathology
Pathogenic Microbiology
Metadata
Show full item recordAbstract
Salmonella enterica subtype Typhimurium (S. Typhimurium) is one of many non-typhoidal Salmonella enterica strains responsible for over one million cases of salmonellosis in the United States each year. These Salmonella strains are also a leading cause of diarrheal disease in developing countries. Nontyphoidal salmonellosis induces gastrointestinal distress that is characterized histopathologically by an influx of polymorphonuclear leukocytes (PMNs), the non-specific effects of which lead to tissue damage and contribute to diarrhea. Prior studies from our lab have demonstrated that the type III secreted bacterial effector SipA is a key regulator of PMN influx during S. Typhimurium infection and that its activity requires processing by caspase-3. Although we established caspase-3 activity is required for the activation of inflammatory pathways during S. Typhimurium infection, the mechanisms by which caspase-3 is activated remain incompletely understood. Most challenging is the fact that SipA is responsible for activating caspase-3, which begs the question of how SipA can activate an enzyme it requires for its own activity. In the present study, we describe our findings that the eukaryotic tetraspanning membrane protein PERP is required for the S. Typhimuriuminduced influx of PMNs. We further show that S. Typhimurium infection induces PERP accumulation at the apical surface of polarized colonic epithelial cells, and that this accumulation requires SipA. Strikingly, PERP accumulation occurs in the absence of caspase-3 processing of SipA, which is the first time we have shown SipA mediates a cellular event without first requiring caspase-3 processing. Previous work demonstrates that PERP mediates the activation of caspase-3, and we find that PERP is required for Salmonella-induced caspase-3 activation. Our combined data support a model in which SipA triggers caspase-3 activation via its cellular modulation of PERP. Since SipA can set this pathway in motion without being cleaved by caspase-3, we propose that PERP-mediated caspase-3 activation is required for the activation of SipA, and thus is a key step in the inflammatory response to S. Typhimurium infection. Our findings further our understanding of how SipA induces inflammation during S. Typhimurium infection, and also provide additional insight into how type III secreted effectors manipulate host cells.DOI
10.13028/M2VS3ZPermanent Link to this Item
http://hdl.handle.net/20.500.14038/32176Rights
Copyright is held by the author, with all rights reserved.ae974a485f413a2113503eed53cd6c53
10.13028/M2VS3Z
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