Importantly, the LPS array can be remodeled in response to environmental conditions such as external pH [68, Selleckchem BI-6727 69]. How then might cholesterol modulate LPS biogenesis and modification? The lipid compositions of the inner and outer membranes of gram negative bacteria are specific and distinct [70], but little is known about the subcellular compartmentation of cholesterol in H. pylori or other prokaryotes. We propose that the presence of cholesterol is needed to establish the proper membrane

composition and structure that permit the orderly building of nascent LPS as it transits across the inner membrane/periplasmic/outer membrane compartments. In this model, altered membrane composition may influence the activity of LPS biosynthetic enzymes embedded in the membrane, leading to improper LPS modification. Alternatively, cholesterol

depletion may result in dysregulation of LPS transporter function due to alterations in membrane structure and composition. The dysregulated movement of LPS among inner membrane, periplasmic, and outer membrane compartments would then result in aberrant modifications to its structure. This scenario would be consistent with the observed discrepancy between whole cell Lewis antigen levels measured by immunoblot and cell surface levels measured by ELISA. That is, it is possible that under cholesterol-depletion the Lewis antigen-bearing LPS may Momelotinib clinical trial be less effectively transported to the cell surface. Preliminary

evidence indicates that membrane cholesterol may also influence certain ABC transporters and the ComB DNA transporter in H. pylori (Hildebrandt, Trainor and McGee, unpublished results). Thus, cholesterol may support a wider range of physiological processes in the bacterial membrane than is currently appreciated. Conclusions We have demonstrated for the first most time that cholesterol, though nonessential to growth of H. pylori, is nevertheless essential for gastric colonization in an animal model. We have further shown that cholesterol plays important roles in determining LPS structure as well as Lewis antigen expression, and that these biological effects are highly specific for cholesterol. LPS profiles of mutant strains lacking the O-chain retain responses to cholesterol availability, providing evidence for structural changes to the oligosaccharide core/lipid A moieties. Disruption of the lipid A 1-phosphatase gene, lpxE, eliminated the effect of cholesterol on LPS profiles, suggesting that aberrant forms of LPS that appear upon cholesterol depletion are dependent upon 1-dephosphorylation of lipid A. The roles of cholesterol in LPS structural modification and in Lewis antigen expression do not require α-glucosylation of cholesterol. Thus, cholesterol imparts these benefits independently of its previously reported role in resistance to host phagocytosis and T-cell responses, which require the alpha-glycoside metabolite of cholesterol [35].