Background: CRP exerts antipneumococcal function in mice if administered during the early stages of pneumococcal infection. Results: CRP loses such antipneumococcal function when its phosphocholine-binding pocket is blocked. Conclusion:The phosphocholine-binding pocket on CRP participates in antipneumococcal function of CRP during the early stages of infection. Significance: Remodeling of CRP may be required for successful treatment of mice during the late stages of infection.

C-reactive protein (CRP) performs two recognition functions that are relevant to cardiovascular disease. First, in its native pentameric conformation, CRP recognizes molecules and cells with exposed phosphocholine (PCh) groups, such as microbial pathogens and damaged cells. PCh-containing ligand-bound CRP activates the complement system to destroy the ligand. Thus, the PCh-binding function of CRP is defensive if it occurs on foreign pathogens because it results in the killing of the pathogen via complement activation. On the other hand, the PCh-binding function of CRP is detrimental if it occurs on injured host cells because it causes more damage to the tissue via complement activation; this is how CRP worsens acute myocardial infarction and ischemia/reperfusion injury. Second, in its nonnative pentameric conformation, CRP also recognizes atherogenic low-density lipoprotein (LDL). Recent data suggest that the LDL-binding function of CRP is beneficial because it prevents formation of macrophage foam cells, attenuates inflammatory effects of LDL, inhibits LDL oxidation, and reduces proatherogenic effects of macrophages, raising the possibility that nonnative CRP may show atheroprotective effects in experimental animals. In conclusion, temporarily inhibiting the PCh-binding function of CRP along with facilitating localized presence of nonnative pentameric CRP could be a promising approach to treat atherosclerosis and myocardial infarction. There is no need to stop the biosynthesis of CRP.

The mechanism of action of C-reactive protein (CRP) in protecting mice against lethal Streptococcus pneumoniae infection is unknown. The involvement of the phosphocholine (PCh)-binding property of CRP in its antipneumococcal function previously has been explored twice, with conflicting results. In this study, using three different intravenous sepsis mouse models, we investigated the role of the PCh-binding property of CRP by employing a CRP mutant incapable of binding to PCh. The ability of wild-type CRP to protect mice against infection was found to differ in the three models; the protective ability of wild-type CRP decreased when the severity of infection was increased, as determined by measuring mortality and bacteremia. In the first animal model, in which we used 25 g of CRP and 10 7 CFU of pneumococci, both wild-type and mutant CRP protected mice against infection, suggesting that the protection was independent of the PCh-binding activity of CRP. In the second model, in which we used 25 g of CRP and 5 ؋ 10 7 CFU of pneumococci, mutant CRP was not protective while wild-type CRP was, suggesting that the protection was dependent on the PCh-binding activity of CRP. In the third model, in which we used 150 g of CRP and 10 7 CFU of pneumococci, mutant CRP was as protective as wild-type CRP, again indicating that the protection was independent of the PCh-binding activity of CRP. We conclude that both PCh-dependent and PCh-independent mechanisms are involved in the CRP-mediated decrease in bacteremia and the resulting protection of mice against pneumococcal infection. Infection with Streptococcus pneumoniae is one of the most common causes of community-acquired pneumonia and septicemia worldwide (reviewed in references 1-3). C-reactive protein (CRP) is a plasma protein whose level in the blood is dramatically increased in patients with S. pneumoniae infection (reviewed in references 4-8). In experiments using animal models, passively administered human CRP, transgenic human CRP, and murine CRP all have been shown to protect mice against lethal infection with S. pneumoniae, as determined by decreased bacteremia and increased survival (9-12). In murine models of infection involving passively administered human CRP, CRP exerted its protective effect only when injected 6 h before to 2 h after the infection but not when mice received CRP 24 h or 36 h postinfection (13,14). Thus, the CRP-mediated protection of mice requires the presence of CRP in the early stages of infection. However, the mechanism of the protective action of CRP in mice during the early stages of infection is not known.CRP binds to pneumococci in both serum and Ca 2ϩ -containing buffers (14). The binding of CRP to pneumococci is mediated via a Ca 2ϩ -dependent interaction between CRP and phosphocholine (PCh) residues present on C-polysaccharide (PnC) of the cell wall of pneumococci (15). Because PnC-complexed CRP activates the complement system in both human and mouse sera (4, 16; reviewed in reference 17), it has been proposed that the mechanism of th...

C-reactive protein (CRP) binds to several species of bacterial pathogens including Streptococcus pneumoniae. Experiments in mice have revealed that one of the functions of CRP is to protect against pneumococcal infection by binding to pneumococci and activating the complement system. For protection, however, CRP must be injected into mice within a few hours of administering pneumococci, that is, CRP is protective against early-stage infection but not against late-stage infection. It is assumed that CRP cannot protect if pneumococci got time to recruit complement inhibitor factor H on their surface to become complement attack-resistant. Since the conformation of CRP is altered under inflammatory conditions and altered CRP binds to immobilized factor H also, we hypothesized that in order to protect against latestage infection, CRP needed to change its structure and that was not happening in mice. Accordingly, we engineered CRP molecules (E-CRP) which bind to factor H on pneumococci but do not bind to factor H on any host cell in the blood. We found that E-CRP, in cooperation with wild-type CRP, was protective regardless of the timing of administering E-CRP into mice. We conclude that CRP acts via two different conformations to execute its anti-pneumococcal function and a model for the mechanism of action of CRP is proposed. These results suggest that pre-modified CRP, such as E-CRP, is therapeutically beneficial to decrease bacteremia in pneumococcal infection. Our findings may also have implications for infections with antibiotic-resistant pneumococcal strains and for infections with other bacterial species that use host proteins to evade complement-mediated killing.

No abstract