Friday, November 22, 2024
11/22/2024
Project Summary / Abstract C-reactive protein (CRP) was discovered in the blood obtained from patients infected with Streptococcus pneumoniae and was found to be a component of innate immunity and inflammatory response. In murine models of infection, human CRP is protective against lethal infection with S. pneumoniae. The mechanisms of anti-pneumococcal action of CRP are not defined yet. Interestingly, CRP was protective only during the early stages of infection, i.e., when CRP was injected into mice within 6 h of administering pneumococci. CRP was not protective during the late stages of infection, i.e., CRP was not protective when injected into mice after 6 h of administering pneumococci. In vitro, CRP binds to phosphocholine groups present in the cell wall C- polysaccharide of pneumococci and subsequently activates the complement system. Accordingly, it is hypothesized that CRP is protective because ligand-bound CRP activates the complement system on the pneumococcal surface leading to the reduction of bacteremia. This hypothesis explains the protective effects of CRP during the early stages of infection, but this does not explain why CRP loses its protective effect during the late stages of infection. We hypothesize that CRP works through two mechanisms: one mechanism based on the binding of CRP to phosphocholine and subsequent complement activation and one mechanism based on the binding of CRP to complement inhibitor factor H. This hypothesis will be tested in the following three specific aims. In aim 1, the hypothesis that “the activation of the complement system on the pneumococcal surface, subsequent to the binding of CRP to pneumococci, participate in CRP-mediated protection” will be tested. In aim 2, two hypotheses that “pneumococci recruit complement inhibitory protein factor H on their surface and evade complement attack during late stage infection” and that “structurally altered CRP capable of binding to factor H can protect mice against infection during the late stages also” will be tested. In aim 3, the hypothesis that “the binding of CRP to phosphocholine groups is critical for complement activation and killing of pneumococci” will be tested. These hypotheses will be tested by using mutants of CRP incapable of activating murine complement, capable of binding to factor H, and incapable of binding to phosphocholine and by employing both wild-type and CRP knockout mice. Successful completion of this project will provide insight into the mechanisms of anti-pneumococcal functions of CRP which may lead to the development of a CRP-based strategy to treat late stage pneumococcal infection.
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