C-reactive protein(CRP), an acute phase reactant, is a normal constituent of human sera. It's function in the serum includes binding to phosphorylcholine (ChoP) on the cell wall of Streptococcus pneumoniae, which leads to activation of the complement pathway and promotion of opsonophagocytosis. In addition to the pneumococcus, ChoP is now known to be a cell-surface feature of many of the major pathogens of the human respiratory tract. This suggest that CRP might be the key component in a previously underappreciated innate defense mechanism that targets these ChoP-expressing pathogens. CRP was though to be produced only by hepatocytes and, in rats, alveolar macrophages have been shown to produce CRP under similar control. The presence and function of CRP on mucosal surfaces in the human respiratory tract secretions using Mab to human CRP and confirming it's ChoP binding specificity. Furthermore, we have demonstrated transcription of the CRP gene in epithelial cells lining the upper airway suggesting that mucosal CRP maybe locally produced. In addition, this protein was found to have bacterial activity in the presence of the complement against ChoP- expressing Haemophiles influenzae. The goal of this proposal is to define the relationship of this protein to serum CRP, characterize the mucosal form of CRP and analyze the role of mucosal CRP in innate immunity of the respiratory tract.
In aim #1, we will characterize the presence and amount of the CRP-like protein in human airway secretions using immunologic (Western Blot and ELISA) and functional (binding to ChoP) analysis.
In aim #2, we will confirm immunologic and functional evidence that the 24kD protein and slightly larger forms with features in airway secretions are CRP and/or modified forms of CRP by peptide sequence analysis.
The third aim will look further at the local expression of CRP in the respiratory tract by epithelial cells and leukocytes, and determine whether mucosal CRP is inducible by cytokines as is the case for CRP of hepatic origin. The last aim will be to define the role that mucosal CRP, purified from the human respiratory tract, plays in innate immunity of the airway using in vitro bactericidal and adherence assays on ChoP-expressing respiratory pathogens. These results will be tested in vivo using murine models of respiratory tract infection with mice carrying the human CRP transgene.
| Gould, Jane M; Weiser, Jeffrey N (2002) The inhibitory effect of C-reactive protein on bacterial phosphorylcholine platelet-activating factor receptor-mediated adherence is blocked by surfactant. J Infect Dis 186:361-71 |
