A virus hosted in malaria-infected blood protects against T cell-mediated inflammatory diseases by impairing DC function in a type I IFN-dependent manner

Abstract

AbstractCo-infections shape the host immune status, thereby influencing the development of inflammatory diseases, which can result in detrimental or beneficial effects. For example, co-infections with concurrent Plasmodium species can alter malaria clinical evolution and malaria infection itself has the ability to modulate autoimmune reactions but, in both cases, the underlying mechanisms remain ill-defined.Here, we demonstrate that the protective effects of certain rodent malaria strains on T cell-mediated inflammatory pathologies are due to an RNA virus co-hosted in malaria-parasitized blood. We show that live as well as extracts of blood parasitized by P. berghei K173 or P. yoelii 17X YM, confer full protection against Pb ANKA (PbA)-induced Experimental Cerebral Malaria (ECM) and MOG/CFA-induced experimental autoimmune encephalomyelitis (EAE), and that this is associated with a strong type I IFN signature. We detected the presence of a viral element, the RNA virus Lactate Dehydrogenase-elevating Virus (LDV), in the protective Plasmodium stabilates and we established that infection with LDV alone recapitulates the protective effects on ECM and EAE. In ECM, we further show that protection results from an IFN-I-mediated reduction in the abundance of splenic conventional dendritic cell and in their ability to produce the Th1-inducing IL-12p70, leading to a decrease in pathogenic CD4+ Th1 responses. In EAE, protection is achieved by IFN-I mediated blunting of IL-12 and IL-23, preventing the differentiation of IFN-γ-, IL-17- and GM-CSF-producing encephalitogenic CD4+ T cells.Thus, our results identify a virus that is co-hosted in several Plasmodium stabilates across the community and has major consequences on the host immune system. Moreover, our data emphasize the importance of considering concurrent infections for the understanding of autoimmunity and malaria-associated inflammatory complications.