INTERACTION OF LIPID A AND INNATE IMMUNE RECEPTORS IN NEISSERIA INFECTION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Infections due to Neisseria gonorrhoeae and N. meningitidis represent a major public health problem around the world. In patients with Neisserial infections, levels of cytokines such as TNF-alpha, IL-1beta, IL-6, and IL-8 are increased relative to the severity of the clinical disease presentation. Two innate immune receptors, toll-like receptor 4 (TLR4) and triggering receptor expressed on myeloid cells (TREM), which are expressed on monocytes, neutrophils, and mucosal epithelial cells, are stimulated by lipopolysaccharide (LPS) from enteric bacteria and are required for an efficient immune response to Gram-negative bacterial infections. Among the important virulence factors involved in the pathogenesis of Neisserial infections, the lipooligosaccharide (LOS) is believed to be a major component inducing host cytokine responses to the organisms. In particular, several studies have implicated the lipid A portion as the bioactive component of Neisserial LOS. We hypothesize that heterogeneity in the acylation and phosphorylation of the lipid A, both of which have been shown to influence the toxicity of LPS from Escherischia coli, underlies the differential reactivity of Neisserial LOS with TLR4 and TREM resulting in differences in degree to which cytokines are induced during infection. Based on the key role of TLR4 and TREM in the recognition of bacterial LPS, it is apparent that in inappropriate response by these innate immune receptors to LOS signals could have important consequences during Neisserial infections, leading to exaggerated response such as gonococcal pelvic inflammatory disease and meningococcal sepsis. In this proposal, we will test the postulate that natural variation in the lipid A structure within the LOS of different Neisserial strains is the major determinant of the degree to which cytokines are induced during infection. To this end, we will determine the structure of the lipid A molecules from Neisserial strains showing variable stimulation of the TLR4 receptor. We will use chemical, gas chromatography, mass spectrometry, and magnetic resonance methods to determine the structures of the lipid A molecules.