Globally, 4-6 million people die of enteric infections each year. Even within the United States, Salmonella and other gastroenteric infections are responsible for millions of illness, thousands of deaths and billion-dollar of expenditure from food recall and hospital associated expenses. The innate immune system is the first line of defense against pathogens. After entering intestinal epithelial cells, enteric microbes encounter phagocytes and generate inflammation. However, our understanding about how phagocytes interact, clear, and generate inflammation only from the enteric pathogen is incomplete. Endosomal systems connect innate to adaptive immunity by degrading the pathogenic microbe and presenting the antigens but our knowledge is limited to their responses to immune signaling. Bacterial recognition by host cells is fundamental for the initiation of mucosal immune responses during the infection process. As a consequence of this interaction, signaling cascades are activated in host cells that lead to inflammatory responses and/or phagocytic clearance of attached bacteria. Previously, we found that BAI1 (Brain Angiogenesis Inhibitor 1) recognizes bacterial lipopolysaccharide (LPS) in a unique mechanism than the well-known Toll like receptor 4 (TLR4). BAI1 binds ELMO1 (EnguLfment and cell Motility protein 1) that facilitates the engulfment of bacteria and induces inflammatory responses. While both pathogenic and commensal-Gram-negative bacteria express lipopolysaccharide (LPS), intestinal phagocytes are able to discriminate commensals from enteric pathogens. Preliminary results show that interactions between bacterial effector molecules and ELMO1 modulate TNF-? production. My general hypothesis is that the sensing of enteric microbes by ELMO1 conduits signaling events that regulate host immune responses. The broad objectives for the proposed studies are to understand the microbial sensing by the host engulfment pathway that generates differential innate responses in the mucosa and the pathogenesis of enteric infections. These objectives will be addressed in the following Specific Aims:
Aim 1 : Define the role of the engulfment pathway in host inflammatory responses.
Aim 2 : Determine the bacterial effectors that regulate the engulfment pathway.
Aim 3 : Define the role of bacterial effector interactions in innate immunity. The proposed studies will delineate the molecular basis whereby a host signaling pathway uptakes enteric pathogens, associates with endosomal signaling and regulates immune responses. As such, they will provide new mechanism involving bacterial effectors in regulating intestinal innate responses that are relevant to Salmonella and other enteric infections. A more complete knowledge of these aspects of microbial interaction with innate immune system will lead to targeted therapies for antimicrobial resistant infections and broadly to limit inflammation-linked diseases.

Public Health Relevance

This proposal is to investigate the innate responses after the engulfment of enteric microbes that interact with host signaling molecule to regulate the inflammation. I propose to examine microbial factors that interact with the host engulfment machinery and contribute to the innate mucosal responses. This study will advance our understanding of intestinal homeostasis and differential immune sensing against commensal microbiota vs enteric pathogens in water- or food-borne enteric infections and broadly to inflammatory diseases; and enhance our ability to design new targeted therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK107585-02
Application #
9336302
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Perrin, Peter J
Project Start
2016-09-01
Project End
2021-08-31
Budget Start
2017-09-01
Budget End
2018-08-31
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of California, San Diego
Department
Pathology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Sahan, Ayse Z; Hazra, Tapas K; Das, Soumita (2018) The Pivotal Role of DNA Repair in Infection Mediated-Inflammation and Cancer. Front Microbiol 9:663
Sarkar, Arup; Tindle, Courtney; Pranadinata, Rama F et al. (2017) ELMO1 Regulates Autophagy Induction and Bacterial Clearance During Enteric Infection. J Infect Dis 216:1655-1666