Phosphorylcholine (ChoP) is found on the surface of many of the potentially invasive pathogens that colonize the mucosal surface of the respiratory tract, including members of the genera Streptococcus, Haemophilus, and Neisseria. However, for each of these species the display of ChoP is phase-variable, suggesting that in some circumstances its expression maybe disadvantageous. During the prior period, we showed that ChoP expressing variants predominate during natural human carriage and are more persistent in animal models of colonization. We propose to examine ChoP-mediated effects that promote bacterial passage through the epithelial barrier as a mechanism that facilitates persistence through evasion of normal mucosal clearance functions and contributes to disease by invasion into tissues. Bacterial expression of ChoP allows for mimicry of host phospholipids such as phosphatidylcholine and platelet activating factor (PAF). For S. pneumoniae and H. influenzae, choline is obtained exclusively from host sources. Since choline is also a nutritional requirement for host cells, choline depletion by bacteria may be an unrecognized source of cytotoxicity.
Aim 1 will examine the effect of bacterial competition for choline with host cells and its contribution to cellular damage and bacterial penetration of epithelial barriers. Mimicry of PAF also allows for attachment to epithelial cells through binding to its receptor, rPAF. PAF has been shown to induce damage to the mucosa.
Aim 2 will examine whether bacterial interaction with rPAF leads to PAF agonist activity that compromises the epithelial barrier. We have shown that ChoP is the target of both innate (C-reactive protein) and adaptive (human ChoP-specific lgG2) immune responses. The effectiveness of antibody to ChoP suggests that ChoP could serve as a common target antigen for protection against pathogens originating in the respiratory tract.
Aim 3 will determine the effects of the immune response to ChoP on colonization, where our findings demonstrate that expression of ChoP is most important to pathogenesis.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Host Interactions with Bacterial Pathogens Study Section (HIBP)
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Khambaty, Farukh M
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University of Pennsylvania
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Langereis, Jeroen D; Weiser, Jeffrey N (2014) Shielding of a lipooligosaccharide IgM epitope allows evasion of neutrophil-mediated killing of an invasive strain of nontypeable Haemophilus influenzae. MBio 5:e01478-14
Langereis, Jeroen D; de Jonge, Marien I; Weiser, Jeffrey N (2014) Binding of human factor H to outer membrane protein P5 of non-typeable Haemophilus influenzae contributes to complement resistance. Mol Microbiol 94:89-106
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Dalia, Ankur B; Weiser, Jeffrey N (2011) Minimization of bacterial size allows for complement evasion and is overcome by the agglutinating effect of antibody. Cell Host Microbe 10:486-96
Davis, Kimberly M; Nakamura, Shigeki; Weiser, Jeffrey N (2011) Nod2 sensing of lysozyme-digested peptidoglycan promotes macrophage recruitment and clearance of S. pneumoniae colonization in mice. J Clin Invest 121:3666-76
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