Food and water-borne infections remain a major global health problem. According to the estimates of the World Health Organization, 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 and thousands of deaths. For example, Salmonella affects 1-2 million Americans each year. However, our understanding about how phagocytes interact and clear the vast, complex populations of enteric bacteria is incomplete. Phagocytes are present as the front line of the immune defense mechanisms to protect our body from microbial pathogens. 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. Bacteria interact with host cells via multiple pattern recognition receptors (PRRs) which recognize microbial products or pathogen-associated molecular patterns (PAMPs). Recently we identified a new pattern recognition receptor, BAI1 (Brain Angiogenesis Inhibitor 1). BAI1 preferentially binds Gram-negative bacteria and contributes to bacterial internalization by activating the ELMO1 (Engulfment and cell motility protein 1)/Rac1 pathway. Moreover, the BAI1/ELMO1/Rac1 pathway regulates innate cytokine responses. Preliminary results show that interactions between bacterial effector molecules and ELMO1 modulate TNF-a production. My general hypothesis is that the recognition of Gram-negative bacteria by BAI1 leads to ELMO1-mediated signaling events that regulate bacterial uptake and the subsequent inflammatory responses. The broad objectives for the proposed studies are to define the molecular basis of bacterial engulfment and determine how this event impacts 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 BAI1/ELMO1/Rac1 pathway in bacterial recognition/internalization.
Aim 2 : Determine the bacterial effectors that regulate the BAI1/ELMO1/Rac1 pathway.
Aim 3 : Define the role of the BAI1/ELMO1/Rac1 in regulating host responses. The proposed studies will define the molecular basis whereby a novel receptor and its associated engulfment pathway uptakes enteric pathogens and regulates subsequent inflammation. As such, they will provide new information to advance our understanding of a 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 pathogenesis may lead to new therapies that limit the translocation of pathogenic bacteria and the tissue damage induced by local inflammatory responses.
This application is to investigate a novel pathway regulating the pathogenesis of enteric infections in general and food-borne infections in particular. I propose to examine virulence factors that interact with the engulfment pathway that may contribute to the host inflammatory responses after infection. Establishing the role of this novel pattern recognition receptor and its associated signaling responses will advance our understanding of the pathogenesis of water- or food-borne enteric infections and enhance our ability to design new therapeutic approaches.