Shigella flexneri are intracytosolic bacterial pathogens that cause bacillary dysentery in humans. Determining how intracytosolic bacteria are detected by the host cell is critical for advancing our understanding of the innate immune system. Infection of the colon by S. flexneri leads to an immune response that triggers recruitment of neutrophils and macrophages into the tissue. When S. flexneri enters macrophages, it activates inflammasomes, leading to pyroptosis, a type of pro-inflammatory cell death. The best studied inflammasome pathway is the canonical NLRP3 inflammasome, which consists of (1) the NOD-like receptor (NLR) NLRP3, (2) the adaptor protein ASC, and (3) the inflammatory caspase-1. A non-canonical inflammasome that consists of caspase-4/5 (caspase-11, in mice) has been described; as yet, no NLR protein has been identified. Activated inflammatory caspases from either pathway activate gasdermin D. Our preliminary data show that during S. flexneri infection NLRP11 is required for efficient cell death as well as caspase-4 and gasdermin D activation in human-derived macrophages, Our data also show that cytosolic LPS (cLPS) is sufficient to trigger NLRP11 dependent cell death in these cells. In addition, my preliminary data show that NLRP11 binds LPS and that NLRP11 and pro-caspase-4 interact independent of LPS. Based on our data, we propose a novel role for NLRP11 in the detection of cLPS in the non-canonical inflammasome pathway. My overall hypothesis is that NLRP11 (1) functions to detect cLPS with caspase-4, (2) binds and activates caspase-4, and (3) is a critical component of the non-canonical inflammasome. I propose to test this hypothesis with the following aims: 1. Define the molecular function of NLRP11 in non-canonical inflammasome activation 2. Define the requirements for the interaction of NLRP11 with caspase-4 3. Determine whether LPS, NLRP11, and caspase-4 form a ternary complex. This proposal will generate mechanistic insights into how NLRP11 acts in the non-canonical inflammasome. It is highly likely to uncover novel functional interactions in the non-canonical inflammasome and deepen our understanding of the innate immune system in general. The proposed studies will be conducted in Dr. Marcia Goldberg's laboratory at Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), with the guidance of my co-sponsor, Dr. Judy Lieberman. Both MGH and HMS are rigorous academic environments with ample resources support my research and career development. I will have many opportunities to formally present my research, attend scientific meetings, and attend career development courses. The proposed studies will provide me with new expertise in microbiology and innate immunology and place me in an ideal position of reaching my career goals of being an independent researcher.

Public Health Relevance

Many bacteria that cause human disease invade human cells. The innate immune system is our first line of defense against these infections, and understanding how it works is critical to developing therapeutics to prevent infection. This project aims to define a novel mechanism by which the innate immune system detects intracellular bacteria.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1)
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Mills, Melody
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Massachusetts General Hospital
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