Bacterial infections are still the major cause of morbidity and mortality, and innate immunity is the first line of host defense against infections. The overall objective of this project is to elucidate how innate immunity protects the host from infections with Gram-positive bacteria and how the host response to bacterial components causes clinical manifestations and pathologic changes associated with infections. This project investigates the main component of Gram-positive bacterial cell walls, peptidoglycan, which can reproduce several major clinical manifestations of bacterial infections. This laboratory has identified a novel family of four pattern recognition proteins in humans that recognize peptidoglycan (PGRPs). These human PGRPs are differentially expressed in the bone marrow, neutrophils, liver, esophagus, tonsils, and thymus, and are highly homologous to the family of 12 insect PGRPs. This project will test the hypothesis that mammalian PGRPs interact with peptidoglycan and bacteria and are involved in innate immunity to bacteria. Specifically, the objective will be to identify the function of PGRPs in mammalian immunity using two approaches: First, it will be determined if PGRP-S knockout mice (generated in this laboratory) are immunodeficient, by testing the following aspects of their immunity: (i) development of lymphoid organs and cells; (ii) susceptibility to infections; (iii) inflammatory responses; (iv) induction of cytokines and chemokines; (v) chemotactic and phagocytic responses; and (vi) antibody responses. Second, the functions of the remaining PGRPs (PGRP-L, PGRP-I-alpha, and PGRP-I-beta) will be determined by identifying: (i) tissues and cell types that express these PGRPs; (ii) subcellular localization of each PGRP; (iii) their ligands; (iv) association of PGRPs with other proteins; (v) ability of these PGRPs to induce acute-phase response and uptake of bacteria; (vi) functional domains of these PGRPs; and (vii) inhibitory effects of soluble PGRP-S on the functions of transmembrane PGRPs. This study may discover a new mechanism of innate immunity and a new immunodeficiency, and may provide tools for developing new preventive and therapeutic measures against infections with Gram-positive bacteria.
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