Shigella, NIAID category B pathogens, cause ~550 million cases of diarrhea or dysentery and 1.1 million deaths each year. Shigella infections are characterized by the induction of acute inflammation associated with a massive recruitment of neutrophils to the colon resulting in subsequent massive tissue destruction. Despite this impressive host response, Shigella survive in this harsh environment, primarily by invading and spreading between colonic epithelial cells. Shigella survival is primarily due to the ability of ths pathogen to directly usurp and regulate host cell processes through the activity of ~30 type 3 effectors, proteins that the bacteria directly injects into the host cell cytosol through its highl conserved type 3 secretion system. The Shigella type 3 secretion system is essential for all steps in Shigella pathogenesis including their invasion of host cells, escape from the phagosome, intracellular and intercellular spread and inhibition of the production of pro-inflammatory cytokines. The overall goal of our research is to understand how Shigella effectors enable this pathogen to evade and suppress host innate immune responses. Specifically we propose to determine the host cell proteins and or processes targeted by type 3 effectors that we have established to be involved in Shigella phagosomal escape and cell-to-cell, two steps in Shigella pathogenesis that are relatively poorly understood. These studies should prove general insights regarding the spread of intracellular bacterial pathogens. We also propose to identify host cell proteins directed ubiquitinated and targeted for degradation by Shigella effectors as these proteins are likely key elements in signaling pathways involved in normally inducing host innate immune defenses that normally act to combat bacterial pathogens. By performing and completing the proposed aims, we expect to greatly expand our understanding of how Shigella and other intracellular pathogens manipulate host cell processes in order to evade host innate immune defenses. This information will have the potential to guide the development of novel therapeutics to prevent and treat infections caused by Shigella and other bacterial pathogens.

Public Health Relevance

Shigella is a human bacterial pathogen that causes a severe diarrhea associated with a significant degree of morbidity and mortality. Our application is aimed at understanding how Shigella utilize virulence proteins to directly manipulate epithelial cells to promote their survival and dissemination by evading host innate immune defenses. The results our studies could lead to the development of novel therapeutics for the prevention and treatment of Shigella and potentially other bacterial pathogens by improving our understanding of how bacteria manipulate host cells.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Host Interactions with Bacterial Pathogens Study Section (HIBP)
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Mills, Melody
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Massachusetts General Hospital
United States
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Ernst, Nadja Heinz; Reeves, Analise Z; Ramseyer, Julia E et al. (2018) High-Throughput Screening of Type III Secretion Determinants Reveals a Major Chaperone-Independent Pathway. MBio 9:
Mou, Xiangyu; Souter, Skye; Du, Juan et al. (2018) Synthetic bottom-up approach reveals the complex interplay of Shigella effectors in regulation of epithelial cell death. Proc Natl Acad Sci U S A 115:6452-6457
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