Leishmania RNA virus exacerbates Leishmaniasis by subverting innate immunity via TLR3-mediated NLRP3 inflammasome inhibition

Abstract

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 ATG5mediated 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.

A novel mycovirus evokes transcriptional rewiring in the fungusMalasseziaand stimulates interferon-β production in macrophages

“…In leishmaniasis, a parasitic disease caused by Leishmania , an elevated burden of Leishmania RNA virus-1 (LRV1) in the parasite is associated with parasite dissemination and increased disease severity (43, 44). Toll-like receptors (TLRs) are innate immune-recognition receptors known to play a role in viral infection, and TLR3, which recognizes and responds to dsRNA (45), was found to be required for the induction of pro-inflammatory factors and disease exacerbation in leishmaniasis (43).…”

“…Due to the role of IFN-β in the stimulation of antiviral and antiproliferative products (54), it is possible that the production of IFN-β may lead to enhanced clearing of virus-infected fungal cells from macrophages. TLR3 binds dsRNA in mammalian cells and was shown to play a critical role in disease exacerbation in leishmaniasis when the infecting Leishmania strain harbors a mycovirus (43, 44). In the case of M. sympodialis , we did not observe a requirement of TLR3 for IFN-β production in response to virus-infected strains (Figure 5B).…”

The First Non-LRV RNA Virus in Leishmania

“…Notably, the clinical manifestations range from asymptomatic infection and various types of lesions to visceral disease. Previously, it was demonstrated that LRV1 boosts virulence of Leishmania guyanensis in humans [33,34,102,103]. The discovery of a virus in L. martiniquensis poses an important question on whether it also influences the pathogenicity of this parasite.…”

Reconciling protective and pathogenic roles of the NLRP3 inflammasome in leishmaniasis

“…infection. A recent study by de Carvalho et al 88 showed that LRV is present within L guyanensis and activates TLR3 to dampen caspase‐1 and IL‐1β production, that is, LRV+ve L guyanensis induces significantly lower levels of caspase‐1 activation and IL‐1β production by BMDM in vitro. In vivo ear infection of C57BL/6 mice with LRV+ L guyanensis resulted in increased swelling and parasite burden when compared to LRV‐ve L guyanensis ; however, these differences between LRV+ve and LRV‐ve L guyanensis are not observed during infection of Nlrp3 −/− mice.…”

“…In reviewing all known articles that show a protective role for the NLRP3 inflammasome, 56,64,76,82,88,89 we noted that these studies exclusively use C57BL/6 mice, and NLRP3 inflammasome‐deficient mice backcrossed to C57BL/6 as mammalian hosts. Regarding Leishmania spp., these studies mostly use new‐world Leishmania spp.…”