A Systems Approach Reveals MAVS Signaling in Myeloid Cells as Critical for Resistance to Ebola Virus in Murine Models of Infection

Abstract

SUMMARY The unprecedented 2013–16 outbreak of Ebola virus (EBOV) resulted in over 11,300 human deaths. Host resistance to RNA viruses requires RIG-I-like receptor (RLR) signaling through the adaptor protein, mitochondrial antiviral signaling (MAVS), but the role of RLR-MAVS in orchestrating anti-EBOV responses in vivo is not known. Here, we apply a systems approach to MAVS−/− mice infected with either wild-type or mouse-adapted EBOV. MAVS controlled EBOV replication through expression of IFNα, regulation of inflammatory responses in the spleen, and prevention of cell death in the liver, with macrophages implicated as a major cell-type influencing host resistance. A dominant role for RLR signaling in macrophages was confirmed following conditional MAVS deletion in LysM+ myeloid cells. These findings reveal tissue-specific MAVS-dependent transcriptional pathways associated with resistance to EBOV, and demonstrate that EBOV adaptation to cause disease in mice involves changes in two distinct events, RLR-MAVS antagonism and suppression of RLR-independent IFN-I responses.

Tilorone: a Broad-Spectrum Antiviral Invented in the USA and Commercialized in Russia and beyond

“…Tilorone causes a rapid increase in the mitochondrial potential (after 30 minutes), which may reflect the activity of the direct downstream signaling partner of RIG-I called the mitochondrial antiviral signaling protein (MAVS) (43). The RLR signaling and the MAVS protein have been shown to be a critical mediator of viral replication in mice (44). In vitro binding data shows that tilorone can directly bind human RIG-I, though only weakly when the assay is performed in a simple buffer with no other cellular components (Fig.…”

The role of mononuclear phagocytes in Ebola virus infection

“…Shed EBOV GP ectodomain, generated from virion‐ and cell‐associated GP that is cleaved with cell surface proteases, was able to activate uninfected macrophages in a TLR‐4 dependent manner resulting in cytokine production (i.e., TNF, IL‐1β, IL‐6, IL‐8, IL‐12p40, IL‐10) and up‐regulation of co‐stimulatory markers . Consistent with this, a number of studies demonstrated that purified EBOV GP, EBOV GP constructs or EBOV VLPs administered to monocytes, macrophages or DCs leads to significant production of proinflammatory cytokines, chemokines and type I interferon responses . Olejnik et al.…”

Control of Nipah Virus Infection in Mice by the Host Adaptors Mitochondrial Antiviral Signaling Protein (MAVS) and Myeloid Differentiation Primary Response 88 (MyD88)

“…The role of several signaling pathways was observed for some other RNA viruses, including VSV [12] or rotavirus [19]. In certain viral infections, however, including Ebola virus or rhinovirus infection, either MAVS or MyD88 signaling alone, respectively, was shown to be sufficient to induce efficient antiviral protection [20,21]. Interestingly, although TLR3/TRIF signaling was shown to be important in certain viral infections [11], it does not seem to be critical in NiV infection in mice.…”