RESUMEN
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RESUMEN
Leishmania RNA virus (LRV) is an important virulence factor associated with the development of mucocutaneous Leishmaniasis, a severe form of the disease. LRV-mediated disease exacerbation relies on TLR3 activation, but downstream mechanisms remain largely unexplored. Here, we combine human and mouse data to demonstrate that LRV triggers TLR3 and TRIF to induce type I IFN production, which induces autophagy. This process results in ATG5-mediated degradation of NLRP3 and ASC, thereby limiting NLRP3 inflammasome activation in macrophages. Consistent with the known restricting role of NLRP3 for Leishmania replication, the signaling pathway triggered by LRV results in increased parasite survival and disease progression. In support of this data, we find that lesions in patients infected with LRV+ Leishmania are associated with reduced inflammasome activation and the development of mucocutaneous disease. Our findings reveal the mechanisms triggered by LRV that contribute to the development of the debilitating mucocutaneous form of Leishmaniasis.
Asunto(s)
Inmunidad Innata/inmunología , Inflamasomas/inmunología , Leishmania/inmunología , Leishmaniasis Mucocutánea/inmunología , Proteína con Dominio Pirina 3 de la Familia NLR/inmunología , Virus ARN/inmunología , Receptor Toll-Like 3/inmunología , Animales , Autofagia/inmunología , Humanos , Interleucina-1beta/inmunología , Interleucina-1beta/metabolismo , Leishmania/fisiología , Leishmania/virología , Leishmaniasis Mucocutánea/parasitología , Leishmaniasis Mucocutánea/virología , Macrófagos/inmunología , Ratones , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Virus ARN/fisiología , Transducción de Señal/inmunología , Receptor Toll-Like 3/metabolismoRESUMEN
Activation of the NLRP3 inflammasome by Leishmania parasites is critical for the outcome of leishmaniasis, a disease that affects millions of people worldwide. We investigate the mechanisms involved in NLRP3 activation and demonstrate that caspase-11 (CASP11) is activated in response to infection by Leishmania species and triggers the non-canonical activation of NLRP3. This process accounts for host resistance to infection in macrophages and in vivo. We identify the parasite membrane glycoconjugate lipophosphoglycan (LPG) as the molecule involved in CASP11 activation. Cytosolic delivery of LPG in macrophages triggers CASP11 activation, and infections performed with Lpg1-/- parasites reduce CASP11/NLRP3 activation. Unlike bacterial LPS, purified LPG does not activate mouse CASP11 (or human Casp4) in vitro, suggesting the participation of additional molecules for LPG-mediated CASP11 activation. Our data identify a parasite molecule involved in CASP11 activation, thereby establishing the mechanisms underlying inflammasome activation in response to Leishmania species.