Activation of mouse complement C3 by human C-reactive protein (134.59)

Abstract

Abstract Human C-reactive protein (CRP), once bound to pneumococcal C-polysaccharide (PnC), interacts with C1q and activates the classical pathway of complement in human serum. In mouse serum also, PnC-bound CRP activates complement, but not through the classical pathway because human CRP does not interact with mouse C1q. This study was undertaken to determine the pathway through which human CRP activates mouse complement and to generate a CRP mutant incapable of activating mouse complement. We found that human CRP could bind to mouse mannose-binding lectins, indicating that human CRP might activate the lectin pathway of complement in mouse serum. Further experiments to investigate whether human serum activates the lectin pathway of complement in mouse serum are ongoing. We next determined the complement C3-activating potential of two CRP mutants, Y175A and L176Q, which do not bind to human C1q. As expected, both CRP mutants did not activate C3 in human seum. However, in mouse serum, the C3-activating potential of the L176Q CRP, but not of Y175A CRP, was drastically reduced compared to that of wild-type CRP. It has been shown previously that human CRP protects mice from lethality following infection with Streptococcus pneumoniae. The L176Q CRP is a useful mutant of CRP to define the contribution of CRP-mediated complement activation in the anti-pneumococcal function of human CRP in mouse models of infection. NIH R01HL071233