Abstract
Leptospirosis is a worldwide re-emerging zoonosis caused by pathogenic Leptospira spp. All vertebrate species can be infected; humans are sensitive hosts whereas other species, such as rodents, may become long-term renal carrier reservoirs. Upon infection, innate immune responses are initiated by recognition of Microbial Associated Molecular Patterns (MAMPs) by Pattern Recognition Receptors (PRRs). Among MAMPs, the lipopolysaccharide (LPS) is recognized by the Toll-Like-Receptor 4 (TLR4) and activates both the MyD88-dependent pathway at the plasma membrane and the TRIF-dependent pathway after TLR4 internalization. We previously showed that leptospiral LPS is not recognized by the human-TLR4, whereas it signals through mouse-TLR4 (mTLR4), which mediates mouse resistance to acute leptospirosis. However, although resistant, mice are known to be chronically infected by leptospires. Interestingly, the leptospiral LPS has low endotoxicity in mouse cells and is an agonist of TLR2, the sensor for bacterial lipoproteins. Here, we investigated the signaling properties of the leptospiral LPS in mouse macrophages. Using confocal microscopy and flow cytometry, we showed that the LPS of L. interrogans did not induce internalization of mTLR4, unlike the LPS of Escherichia coli. Consequently, the LPS failed to induce the production of the TRIF-dependent nitric oxide and RANTES, both important antimicrobial responses. Using shorter LPS and LPS devoid of TLR2 activity, we further found this mTLR4-TRIF escape to be dependent on both the co-purifying lipoproteins and the full-length O antigen. Furthermore, our data suggest that the O antigen could alter the binding of the leptospiral LPS to the co-receptor CD14 that is essential for TLR4-TRIF activation. Overall, we describe here a novel leptospiral immune escape mechanism from mouse macrophages and hypothesize that the LPS altered signaling could contribute to the stealthiness and chronicity of the leptospires in mice.
Highlights
Leptospira spp. are the causative agents of leptospirosis, a neglected global zoonosis
Leptospires are stealth pathogens known to escape the innate immune defenses of their hosts. They are covered in lipopolysaccharide (LPS), a bacterial motif recognized in mammals through the Toll-like receptor 4 (TLR4), which triggers two different signaling pathways
Immunofluorescence analysis of RAW264.7 cells stimulated for 1 h with LPS of the pathogenic L. interrogans strain Verdun revealed that mouse-Toll-Like-Receptor 4 (TLR4) remained localized on the plasma membrane, in contrast to stimulation with E. coli LPS, after which mTLR4 localization was intracellular (Fig 1A)
Summary
Leptospira spp. are the causative agents of leptospirosis, a neglected global zoonosis. Like Borrelia burgdorferi and Treponema pallidum, respective agents of Lyme disease and syphilis, Leptospira spp. possess a lipopolysaccharide (LPS) as one of their outer membrane components [6] This LPS is an essential molecule for the bacterial outer membrane integrity and is known to contribute to leptospiral virulence [7]. Among the various genes of the locus, glycosyl transferases and integral membrane proteins involved in full-length LPS transport were identified as well as enzymes for rhamnose sugar biosynthesis [17] Most of these open reading frames encode proteins of unknown function and the overall structure of the O antigen section of the leptospiral LPS remains unknown. LPS of saprophytic species of Leptospira was found to be short, not completely rough [11]
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