Leptospira interrogans prevents macrophage cell death and pyroptotic IL1β release through its atypical lipopolysaccharide

Abstract

Leptospira interrogans are bacteria that can infect all vertebrates and are responsible for leptospirosis, a neglected zoonosis. Some hosts are susceptible to leptospirosis whereas mice are resistant and get chronically colonized. Although leptospires escape recognition by some immune receptors, they activate NLRP3-inflammasome and trigger IL1β secretion. Classically, IL1β secretion is associated with lytic inflammatory cell death called pyroptosis, resulting from cytosolic LPS binding to inflammatory caspases. Interestingly, we showed that L. interrogans do not trigger cell death in either murine, human, hamster or bovine macrophages, escaping both pyroptosis and apoptosis. Strikingly, we also revealed in murine cells, a potent antagonistic effect of leptospires and their atypical LPS on spontaneous and E. coli LPS induced cell death. The leptospiral LPS efficiently prevents caspase 11 dimerization and subsequent gasdermin D cleavage. Finally, we showed that pyroptosis escape by leptospires prevents massive IL1β release, and we consistently found no major role of IL1 Receptor in controlling experimental leptospirosis in vivo. Overall, our findings described a novel mechanism by which leptospires dampen inflammation, thus potentially contributing to their stealthiness.

Leptospiral lipopolysaccharide dampens inflammation through upregulation of autophagy adaptor p62 and NRF2 signaling in macrophages

“…Indeed, we previously showed that leptospiral LPS avoids human TLR4 and mouse TLR4-TRIF activation. Recently, through the atypical structures of its lipid A and O antigen [11, 47, 48], LPS has also been shown to prevent cell death by pyroptosis. Therefore, it was not surprising to attribute the autophagy modulation phenotype to leptospiral LPS.…”