Lymphocytic Choriomeningitis Virus Differentially Affects the Virus- Induced Type I Interferon Response and Mitochondrial Apoptosis Mediated by RIG-I/MAVS

Arenaviruses are important emerging human pathogens maintained by noncytolytic persistent infection in their rodent reser-voir hosts. Despite high levels of viral replication, persistently infected carrier hosts show only mildly elevated levels of type I interferon (IFN-I). Accordingly, the arenavirus nucleoprotein (NP) has been identified as a potent IFN-I antagonist capable of blocking activation of interferon regulatory factor 3 (IRF3) via the retinoic acid inducible gene (RIG)-I/mitochondrial antiviral signaling (MAVS) pathway. Another important mechanism of host innate antiviral defense is represented by virus-inducedmi-tochondrial apoptosis via RIG-I/MAVS and IRF3. In the present study, we investigated the ability of the prototypic OldWorld arenavirus lymphocytic choriomeningitis virus (LCMV) to interfere with RIG-I/MAVS-dependent apoptosis. We found that LCMV does not induce apoptosis at any time during infection. While LCMV efficiently blocked induction of IFN-I via RIG-I/ MAVS in response to superinfection with cytopathic RNA viruses, virus-inducedmitochondrial apoptosis remained fully active in LCMV-infected cells. Notably, in LCMV-infected cells, RIG-I was dispensable for virus-induced apoptosis via MAVS. Our study reveals that LCMV infection efficiently suppresses induction of IFN-I but does not interfere with the cell’s ability to un-dergo virus-inducedmitochondrial apoptosis as a strategy of innate antiviral defense. The RIG-I independence of mitochondrial apoptosis in LCMV-infected cells provides the first evidence that arenaviruses can reshape apoptotic signaling according to their needs