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Journal Articles Microbes and Infection Year : 2024

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

Abstract

Leptospira interrogans are pathogenic bacteria responsible for leptospirosis, a worldwide zoonosis. All vertebrates can be infected, and some species like humans are susceptible to the disease whereas rodents such as mice are resistant and become asymptomatic renal carriers. Leptospires are stealth bacteria that are known to escape several immune recognition pathways and resist killing mechanisms. We recently published that leptospires may survive intracellularly in and exit macrophages, avoiding xenophagy, a pathogen-targeting form of autophagy. Interestingly, the latter is one of the antimicrobial mechanisms often highjacked by bacteria to evade the host immune response. In this study we explored whether leptospires subvert the key molecular players of autophagy to facilitate infection. We showed in macrophages that leptospires triggered a specific accumulation of autophagy-adaptor p62 in puncta-like structures, without altering autophagic flux. We demonstrated that Leptospira-induced p62 accumulation is a passive mechanism depending on the leptospiral virulence factor LPS signaling via TLR4/TLR2. p62 is a central pleiotropic protein, also mediating cell stress and death, via the translocation of transcription factors. We demonstrated that Leptospira-driven accumulation of p62 induced the translocation of transcription factor NRF2, a key player in the anti-oxidant response. However, NRF2 translocation upon Leptospira infection did not result as expected in antioxydant response, but dampened the production of inflammatory mediators such as iNOS/NO, TNF and IL6. Overall, these findings highlight a novel passive bacterial mechanism linked to LPS and p62/NRF2 signaling that decreases inflammation and contributes to the stealthiness of leptospires.
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pasteur-04600407 , version 1 (04-06-2024)

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Delphine Bonhomme, Ignacio Santecchia, Pedro Escoll, Stylianos Papadopoulos, Frédérique Vernel-Pauillac, et al.. Leptospiral lipopolysaccharide dampens inflammation through upregulation of autophagy adaptor p62 and NRF2 signaling in macrophages. Microbes and Infection, 2024, 26 (3), pp.105274. ⟨10.1016/j.micinf.2023.105274⟩. ⟨pasteur-04600407⟩

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