In humans, CRP is the most characteristic acute-phase protein, since its concentration in the blood rises by as much as 1000-fold within hours from infection or tissue injury. The objective of the proposed research is to define the biologic role of CRP. Our working hypothesis is that the function of CRP relates to its ability to specifically recognize foreign pathogens and damaged or necrotic cells of the host and to initiate their elimination by interacting with the complement system and with phagocytic cells. We propose to approach our objective by pursuing the following specific aims: l) Define the structural correlates of CRP function. The topology and chemical nature of the phosphocholine, fibronectin, Clq, C4, and, neutrophil receptor binding sites will be described by using site- directed mutagenesis as well as protein chemistry and monoclonal antibodies. Parallel collaborative crystallographic studies will aim at producing a solution for the three-dimensional structure of the molecule. 2) Investigate the in-vivo protective effects of CRP against bacterial infections by using human CRP transgenic mice. The range of bacterial species over which CRP-dependent protection extends will be investigated by using a variety of gram-positive and gram-negative bacteria. The mechanisms of protection will be studied by determining sites and rates of bacterial clearance. In addition, the molecular basis for the CRP- dependent protection against pneumococcal infections will be investigated by passive administration of recombinant CRP mutants defective in individual CRP functions. These combined studies will lead to an increased understanding of host- defense mechanisms against bacterial pathogens and other injurious stimuli.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI015607-15
Application #
2060244
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Project Start
1979-01-01
Project End
1998-04-30
Budget Start
1994-05-01
Budget End
1995-04-30
Support Year
15
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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Szalai, A J; van Ginkel, F W; Dalrymple, S A et al. (1998) Testosterone and IL-6 requirements for human C-reactive protein gene expression in transgenic mice. J Immunol 160:5294-9
Agrawal, A; Lee, S; Carson, M et al. (1997) Site-directed mutagenesis of the phosphocholine-binding site of human C-reactive protein: role of Thr76 and Trp67. J Immunol 158:345-50
Szalai, A J; Briles, D E; Volanakis, J E (1996) Role of complement in C-reactive-protein-mediated protection of mice from Streptococcus pneumoniae. Infect Immun 64:4850-3
Szalai, A J; Briles, D E; Volanakis, J E (1995) Human C-reactive protein is protective against fatal Streptococcus pneumoniae infection in transgenic mice. J Immunol 155:2557-63
Agrawal, A; Volanakis, J E (1994) Probing the C1q-binding site on human C-reactive protein by site-directed mutagenesis. J Immunol 152:5404-10
Agrawal, A; Xu, Y; Ansardi, D et al. (1992) Probing the phosphocholine-binding site of human C-reactive protein by site-directed mutagenesis. J Biol Chem 267:25353-8
Kilpatrick, J M; Gresham, H D; Griffin Jr, F M et al. (1987) Peripheral blood mononuclear leukocytes release a mediator(s) that induces phagocytosis of C-reactive protein-coated cells by polymorphonuclear leukocytes. J Leukoc Biol 41:150-5
Horowitz, J; Volanakis, J E; Briles, D E (1987) Blood clearance of Streptococcus pneumoniae by C-reactive protein. J Immunol 138:2598-603
Gresham, H D; Clement, L T; Volanakis, J E et al. (1987) Cholera toxin and pertussis toxin regulate the Fc receptor-mediated phagocytic response of human neutrophils in a manner analogous to regulation by monoclonal antibody 1C2. J Immunol 139:4159-66

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