Chlamydia virulence: exploitation of host N-glycosylation

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 DESCRIPTION (provided by applicant): Chlamydial infections have significant impact on human health. Chlamydia trachomatis is the leading cause of sexually transmitted disease in the United States and preventable blindness in low income nations. In women, the consequences of untreated infection with C. trachomatis can be severe resulting in pelvic inflammatory disease, tubal factor infertility and ectopic pregnancy. Despite significant advances in understanding the immunobiology of chlamydial infection, there are no vaccines available. Although antibiotics are effective in treating acute infections, asymptomatic infection is common and chronic infections are difficult to treat. Thus, elucidating the interactions of this obligate intracellular parasite with the host is fundamental to identifying novel strategies for prevention intervention. A major research focus in our laboratory has been on chlamydial ligand/host receptor interactions. To this end, we have determined that the chlamydial glycan, which is an N- linked high mannose oligosaccharide on the major outer membrane protein (MOMP), plays a key role in attachment and infectivity through interaction with the host mannose receptor. Significantly, removal of the glycan or pretreatment with mannose oligosaccharides to interfere with attachment of the organism to the host significantly decreases infectivity and lung burden or shedding in mouse models of lung and genital tract infections, respectively. These findings support the potential for development of "anti-adhesive therapy" for prevention of infection. An alternative or complementary approach would be to prevent glycosylation of the chlamydial MOMP. The structure of the Chlamydia glycan is analogous to the N-glycans produced by the highly ordered N-glycosylation process in the host. At either the genomic or proteomic level, no chlamydial homologs have been found for the requisite proteins for N-glycosylation. Supported by these observations, the hypothesis to be tested is that the chlamydial MOMP is glycosylated by the host machinery and that Chlamydia recruits the machinery to the vacuole within the host that it resides. A corollary to this hypothesis that will be tested is that inhibitors of host N-glycosylation that inhibit chlamydial infectivity in vitro will decrease lung burden or vaginal shedding in mouse models of lung infection and genital tract infection, respectively. These studies may provide the foundation for development of future strategies to interfere with chlamydial infection.