C REACTIVE PROTEIN IN HOST DEFENSE

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DESCRIPTION (Adapted from applicant's abstract): C-Reactive Protein transgenic (CRPtg) mice mount acute phase human CRP responses, which protect against lethal infection with pneumococci. The long term objective of the proposed research is to define the mechanisms for this CRP-dependent host defense function. Our working hypotheses are: 1) CRP contributes to pre-immune host defense by binding to pathogens, thus targeting them for clearance via complement activation and Fc receptor (FcR)-mediated phagocytosis. 2) Activation of complement by CRP leads to deposition of C3 fragments on bacteria, leading to enhanced protective antibody responses. A similar effect is mediated by CRP-coated antigens binding to FcR on antigen-presenting cells. 3) These events depend on rapid induction of the CRP gene, in proportion to the levels of its hormonally-regulated constitutive expression. These hypotheses will be tested using CRPtg mice and their hybrids genetically deficient in the complement proteins C3 and factor B, in the ^H-chain of FcR, and in interleukin-6. The extent of protection from pneumococci, meningococci, and salmonellae, effected by serum CRP and CRP present in the lungs, will be determined. Model thymus-dependent and -independent antigens will be used to investigate the effects of CRP on the anti-bacterial antibody response. Finally the role of sex hormones, dexamethasone, growth hormone, and complement protein fragments in CR gene regulation will be investigated. These studies will increase the understanding of innate host defense mechanisms and their interaction with acquired immunity.