Complement-mediated anti-pneumococcal functions of C-reactive protein

East Tennessee State University, Johnson City TN

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Abstract

? DESCRIPTION (provided by applicant): C-reactive protein (CRP) was discovered in the blood obtained from patients infected with Streptococcus pneumoniae and was later found to serve as an important component of the innate immune system. In murine models of infection, human CRP is protective against lethal infection with S. pneumoniae. However, 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 cell wall C- polysaccharide of pneumococci and activates the complement system. Accordingly, it is hypothesized that CRP is protective because liganded 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. Our goal is to define the mechanisms by which CRP functions in pneumococcal infection. We hypothesize that CRP works through two different mechanisms, both based on the regulation of the complement system, which will be tested separately in the following two specific aims. In aim 1, the hypothesis that the activation and recruitment of the complement components on the pneumococcal surface, subsequent to the binding of CRP to pneumococci, participate in CRP-mediated protection against pneumococcal infection will be tested. In aim 2, the hypothesis that structurally altered CRP capable of binding to complement factor H can protect mice against infection during the late stages also will be tested. This hypothesis is based on the following two findings: 1. Pneumococci are able to recruit factor H, an inhibitor of complement activation, on their surface, and thus can escape complement-mediated killing. 2. Our recent findings that CRP, in a modified structural form, is capable of binding to immobilized, but not fluid-phase, factor H, the protein that pneumococci bind to and use to escape complement-mediated killing. The overall goals of this proposal are to define the roles of the complement-activating and factor H-binding capabilities of CRP in the protective effects of CRP in pneumococcal infection and to gain insight into the utilization of complement proteins by CRP to function as an anti-pneumococcal molecule which may lead to the development of a CRP-based strategy to treat late stage pneumococcal infection.