Bacterial infections are still the major cause of morbidity and mortality, and innate immunity is the first line of host defense against infections. The long-term objectives of this project are to elucidate how innate immunity protects the host from bacterial infections, how these infections can be prevented, how defects in innate immunity may result in pathologic conditions, and how development of these pathologic conditions can be prevented. This project will investigate a novel family of four pattern recognition molecules, peptidoglycan recognition proteins (PGLYRPs), that were discovered by this laboratory and recently identified as either hydrolytic for peptidoglycan (the major component of bacterial cell wall), or bactericidal for both Gram- positive and Gram-negative bacteria. Bactericidal PGLYRPs are expressed on the skin, in the eyes, on mucous membranes in the oral cavity and gastrointestinal tract, and in sweat, sebum, saliva, and polymorphonuclear leukocytes. The goal of this project is to determine the in vivo role of mammalian PGLYRPs, and specifically, based on in vitro activities of these proteins, to test two hypotheses: (a) that bactericidal PGLYRPs play a role in protecting the host against infections, and (b) that bactericidal and peptidoglycan-hydrolytic PGLYRPs play a scavenger role and protect the host from excessive inflammation induced by bacteria and their peptidoglycan component. These hypotheses will be tested by constructing and using mice deficient in each of these four PGLYRPs, and also mice deficient in multiple PGLYRPs (two, three, or all four PGLYRPs).
The specific aims of this project will be to determine whether these mice have changed sensitivity to infections or changed responsiveness in the following inflammation or immune response models: (i) sensitivity to intestinal, eye, skin, intranasal lung, and systemic intraperitoneal infections;(ii) incidence and severity of experimentally-induced colitis, a model of inflammatory bowel disease caused by overgrowth of intestinal bacteria and increased inflammation induced by bacterial products;(iii) peptidoglycan-induced arthritis;(iv) peptidoglycan-induced experimental autoimmune encephalitis;and (v) adjuvant activity of peptidoglycan for antibody response. This project may discover new mechanisms of resistance to infections, new susceptibility genes for inflammatory bowel disease, and new mechanisms of regulation of bacterially-induced arthritis, encephalitis, and antibody responses.
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