C-reactive protein increases cytokine responses to Streptococcus pneumoniae through interactions with Fcγ receptors

Streptococcus pneumoniae is the most common organism responsible for community acquired pneumonia and meningitis. In pneumococcal pneumonia, a strong local inflammatory cytokine response reduces the frequency of bacteremia and increases survival. The initiation of this cytokine response by innate recognition of bacterial cell wall components through TLR has been described, but the role of soluble innate mediators has received limited attention. C-reactive protein (CRP) is an acute phase protein that binds phosphocholine residues on S. pneumoniae cell walls. CRP interacts with phagocytic cells through Fc gamma RI and Fc gamma RII and activates the classical complement pathway. CRP is protective in mouse pneumococcal bacteremia by increasing complement-dependent clearance and killing of bacteria. We studied the cytokine response of PBMC stimulated with CRP-opsonized S. pneumoniae to determine the effect of CRP interaction with Fc gamma R. CRP dramatically increased the production of TNF-alpha and IL-1 beta in response to S. pneumoniae. These increases were blocked by phosphocholine, which inhibits CRP binding to S. pneumoniae, by inhibitors of Fc gamma R signaling, and by mAb to Fc gamma RI and Fc gamma RII. A mutated rCRP with decreased Fc gamma R binding had a decreased ability to stimulate TNF-a release, compared with wild-type CRP. Individuals who were homozygous for the R-131 allele of Fc gamma RIIA, which has a higher affinity for CRP, showed higher responses to CRP-opsonized, bacteria than did individuals homozygous for the H-131 allele, further implicating this receptor. The results indicate that CRP recognition of S. pneumoniae and binding to Fc gamma R may enhance the early protective cytokine response to infection.