Innate Immunity to Salmonella Infections

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DESCRIPTION (provided by the applicant): Salmonella are one of the most important causes of gastrointestinal infections. The overall goal of our research is to understand how the innate immune response helps to protect against salmonella infections. The first aspect of innate immunity that we will study is PMNs. We previously reported that human epithelial cells make the potent chemotactic peptide IL-8 when invaded by salmonella, which implies that PMNs are important for the host defense against this pathogen. We then showed that PMNs are crucial for defense against salmonella that have virulence plasmids, but not those without virulence plasmids. This proposal focuses on the role of PMNs in protecting the intestine from salmonella infections, using a model of oral infection in mice. The role of PMNs will be established by making mice neutropenic with a monoclonal antibody (RB6-8C5) to the Ly-6G antigen that is specific for myelocytes. We will look for evidence that one or both chemokines are made in vivo in infected mice and in vitro using both cultured murine intestinal epithelial cells and colon organ culture. The second component of the innate immune response that we will investigate is lipopolysaccharide binding protein (LBP). We have confirmed the report by Jack et al (Nature, 389,742,1997) that LBP-deficient mice are more susceptible to salmonella infections, but the mechanism of action of LBP has not been elucidated in infection. We used mice that had the wild-type Nramp1 allele so are genetically resistant to salmonella infections. LBP deficient mice had lower levels of 2 ELR+ CXC chemokines. We will now study the role of CXC chemokines in host resistance to Salmonella by blocking the CXC receptor with antibody. The third goal is to determine whether complement mediated phagocytosis is critical for early resistance to salmonella infections. We will study the course of infection in mice that are deficient in C3 and determine whether neutropenia makes them more susceptible to infection. We will compare isogenic strains of salmonella that express either the group B or 0 LPS antigens in C3 deficient and neutropenic mice, in order to determine how the structure of the LPS affects virulence in mice.