C-Reactive Protein Enhances Immunity to Streptococcus pneumoniae by Targeting Uptake to FcγR on Dendritic Cells

Abstract

C-reactive protein (CRP) is an acute phase reactant with roles in innate host defense, clearance of damaged cells, and regulation of the inflammatory response. These activities of CRP depend on ligand recognition, complement activation, and binding to FcγR. CRP binds to phosphocholine in the Streptococcus pneumoniae cell wall and provides innate defense against pneumococcal infection. These studies examine the effect of this early innate defense molecule on the development of Abs and protective immunity to S. pneumoniae. Dendritic cells (DC) initiate and direct the adaptive immune response by integrating innate stimuli with cytokine synthesis and Ag presentation. We hypothesized that CRP would direct uptake of S. pneumoniae to FcγR on DC and enhance Ag presentation. CRP opsonization of the R36a strain of S. pneumoniae increased the uptake of bacteria by DC. DC pulsed with untreated or CRP-opsonized R36a were transferred into recipient mice, and Ab responses were measured. In mice challenged with free R36a, CRP opsonization resulted in higher secondary and memory IgG responses to both phosphocholine and pneumococcal surface protein A. Furthermore, mice immunized with DC that had been pulsed with CRP-opsonized R36a showed increased resistance to intranasal infection with virulent S. pneumoniae. The effects of CRP on Ag uptake, Ab responses, and protection from infection all required FcR γ-chain expression on DC. The results indicate that innate recognition by CRP enhances effective uptake and presentation of bacterial Ags through FcγR on DC and stimulates protective adaptive immunity.

Fc receptors: Cell activators of antibody functions

“…These reports suggest that these pentraxin proteins behave like antibodies recognizing foreign antigens on pathogens and directing them to cells of the innate immune system [16]. In support of this idea, it was also found that Fcγ receptor uptake of CRP-opsonized Streptococcus pneumoniae increased the immune response against these bacteria [95]. Moreover, CRP also seems to have an anti-inflammatory effect mediated by Fcγ receptors.…”

“…Two members of the pentraxin superfamily [91], which are multimeric cyclic proteins, are reported to bind human and mouse Fcγ receptors. These pentraxins are C-reactive protein (CRP) and serum amyloid P (SAP) [92][93][94][95]. These proteins are usually not found in serum of healthy individuals, but they are rapidly expressed in large amounts during inflammation and microbial infections.…”

The Phosphocholine-binding Pocket on C-reactive Protein Is Necessary for Initial Protection of Mice against Pneumococcal Infection

“…CRP has been shown to enhance uptake and presentation of pneumococcal antigens through Fc␥R on dendritic cells in vitro (43). However, we did not characterize mutant CRP for binding to Fc␥R because Fc␥R do not participate in CRP-mediated protection of mice against pneumococcal infection (44).…”

Acute Phase Proteins: Structure and Function Relationship

“…CRP was found to bind to a ligand on Leishmania donovani and phosphorylcholine-expressing Neisseria meningitides, and hence increase their uptake by human phagocytes (Culley et al, 1996, Casey et al, 2008. Thomas-Rudolph et al (2007) have also reported that innate recognition by CRP enhances effective uptake and presentation of bacterial antigens through Fc-gamma receptors on dendritic cells and stimulates protective adaptive immunity. CRP has been shown to express multiple antiinflammatory effects on neutrophils.…”