We have shown that choline phosphate or phosphorylcholine (ChoP) is found on the surface of numerous bacterial species. In particular, many of the major pathogens that colonize the mucosal surface of the respiratory tract, including members of the genera Streptococcus, Haemophilus, Neisseda and Actinobacillus, express this otherwise unusual prokaryotic structure. We have relied on comparisons of isogenic ChoP+ and ChoP- mutants of H. influenzae to define the contribution of bacterial ChoP to colonization and the pathogenesis of disease. Where possible we have extended our findings to the leading pathogen, S. pneumoniae. Bacterial expression of ChoP allows for mimicry of host phospholipids. For each of the above genera, choline is obtained exclusively from host sources. Since choline is also a nutritional requirement for host cells, choline depletion by bacteria may be a previously unrecognized source of cytopathic effect.
Specific Aim One will examine the effect of competition for choline on host cells. Progress during the previous funding period showed that bacterial ChoP reduces susceptibility to antimicrobial peptides that target differences between host and microbial membranes. Moreover, bacterial ChoP mimicry of platelet-activating factor (PAF) allows for attachment to epithelial cells through binding to its receptor, rPAF. Since PAF is a mediator of inflammation and cell-signaling events, interaction with rPAF could render host clearance mechanisms more permissive for bacterial survival. Such an effect could explain why multiple species utilize this common receptor.
Specific Aim Two will determine the effect of bacterial adherence via ChoP on this receptor and rPAF-mediated signaling events. The expression of ChoP is highly variable suggesting that in some circumstances its expression is disadvantageous for bacterial survival. We have shown that ChoP is the target of both innate (C-reactive protein, which is present on the airway surface) and adaptive (human ChoP-specific IgG2) immune responses. The effectiveness of antibody to ChoP suggests that ChoP could serve as a common target antigen for protection against respiratory tract pathogens.
Specific Aim Three will determine the effects of the immune response to ChoP on colonization, since there is a selection for ChoP-expressing bacteria during carriage, including natural human carriage.
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