Leptospira interrogans (L. interrogans) are pathogenic spirochetal bacteria responsible for a worldwide zoonosis. Rodents are asymptomatic renal carriers of the bacteria and excrete them in their urine, contaminating the environment. Hosts are infected through penetration of motile Leptospira through abraded skin or mucosa. Humans can develop a mild or a severe acute disease with kidney, liver and heart failure. Spirochetes cell walls are peculiar, with 2 membranes, rich in lipoproteins, separated by a periplasmic space, enclosing a peptidoglycan layer that confers the spiral shape and 2 endoflagella allowing the motility. Of note, lipopolysaccharide (LPS), not present in other spirochetes, is constitutive of outer membranes of L. interrogans.
Our research aims to understand the role of pattern recognition receptors (PRRs) including Toll-like receptors (TLRs) and Nod-like receptors (NLRs) in the host immune response against pathogenic Leptospira interrogans. We are trying to understand how this pathogen, and more specifically how peculiarities of cell wall components may overcome the innate immunity defense to allow the escape of L. interrogans from blood defense and colonization of kidneys, that we recently characterized in mice using bioluminescent Leptospira species . We initially found that L. interrogans possess a peculiar lipopolysaccharide that is recognized by TLR2 and not by TLR4 in human cells . Indeed, the lipid A structure is atypical , and not recognized by the human TLR4 receptor, but perfectly sensed by the mouse TLR4 , giving a first hint why mice are resistant to acute leptospirosis whereas humans and TLR4 ko mice are sensitive . Also in mice, leptospiral LPS together with another cell wall component, acting on the potassium pump, trigger the NLRP3 inflammasome activation and subsequent secretion of IL1ß , a potent cytokine involved in inflammation and clearance of bacteria .
Current projects include the study of recognition of leptospiral peptidoglycan, flagellins and the role of other membrane components in the escape from the innate immune response, using macrophage and epithelial cells lines, murine bone marrow and human blood derived macrophages or dendritic cells, and transgenic and KO mice for PRRs or cell subsets.
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