Endosymbiotic RNA virus inhibits Leishmania-induced caspase-11 activation

New World species of the intracellular protozoan parasites of the Leishmania genus can cause mucocutaneous leishmaniases. The presence of an endosymbiotic Leishmania RNA virus (LRV) in Leishmania guyanensis (L.g.) promotes disease exacerbation and the development of mucocutaneous disease. It was previously reported that LRV blocks the NLRP3 inflammasome, but additional mechanisms remain unclear. Here, we investigated whether LRV interferes with the inflammasome via caspase-11, which induces non-canonical NLRP3 activation and was reported to be activated by Leishmania. By using macrophages and mice, we found that LRV inhibits caspase-11 activation and IL-1β release by L.g. in a TLR3- and ATG5-dependent manner. Moreover, LRV exacerbates disease in C57BL/6 mice but not in Casp11(−/−), Nlrp3(−/−), and 129 mice, a mouse strain that is naturally mutant for caspase-11. These results demonstrate that LRV interferes with caspase-11 activation by Leishmania, expanding our understanding about the mechanisms by which LRV promotes disease exacerbation.