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

Abstract

IMPORTANCEArenaviruses are important emerging human pathogens that are maintained in their rodent hosts by persistent infection. Persistent virus is able to subvert the cellular interferon response, a powerful branch of the innate antiviral defense. Here, we investigated the ability of the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) to interfere with the induction of programmed cell death, or apoptosis, in response to superinfection with cytopathic RNA viruses. Upon viral challenge, persistent LCMV efficiently blocked induction of interferons, whereas virus-induced apoptosis remained fully active in LCMV-infected cells. Our studies reveal that the persistent virus is able to reshape innate apoptotic signaling in order to prevent interferon production while maintaining programmed cell death as a strategy for innate defense. The differential effect of persistent virus on the interferon response versus its effect on apoptosis appears as a subtle strategy to guarantee sufficiently high viral loads for efficient transmission while maintaining apoptosis as a mechanism of defense.T he arenaviruses are a large family of emerging viruses that includes several causative agents of severe viral hemorrhagic fevers with high mortality in humans (1, 2). Moreover, the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) provides a powerful experimental system for the discovery of fundamental concepts of virus-host interaction and viral immunobiology applicable to other pathogens (3, 4). Arenaviruses are enveloped negative-strand RNA viruses whose nonlytic life cycle is restricted to the cytoplasm (1). The viral genome is comprised of two RNA segments that code for two proteins each, using an ambisense coding strategy. The small (S) RNA segment encodes the envelope glycoprotein precursor (GPC) and the nucleoprotein (NP), and the L segment encodes the matrix protein (Z) and the viral polymerase (L).In their natural reservoir hosts, arenaviruses are maintained by persistent infection via vertical transmission from infected mothers to offspring in utero (1). Infection with LCMV of most mouse strains within 24 h of birth, prior to negative selection of T cell and B cell repertoires, results in tolerance and the establishment of a largely asymptomatic carrier state (3). Despite extensive viral replication and high viral loads throughout organs and tissues (5), LCMV carrier mice show only a modest type I interferon (IFN-I) response (6), suggesting that arenaviruses evade or actively suppress, or both, innate immunity (7). Major pathogen recognition receptors (PRRs) implicated in innate detection of arenaviruses in many cell types are the cytosolic RNA helicases (RLHs) retinoic

A Map of the Arenavirus Nucleoprotein-Host Protein Interactome Reveals that Junín Virus Selectively Impairs the Antiviral Activity of Double-Stranded RNA-Activated Protein Kinase (PKR)

“…Intriguingly, arenaviruses appear to be highly selective in their antagonism of these innate immune pathways. For example, Pythoud et al demonstrated that despite blocking RIG-I/MAVS-dependent type I IFN production, LCMV leaves MAVS-dependent apoptosis fully functional (47). Likewise, we report here that JUNV can block activated PKR from phosphorylating eIF2␣ ( Fig.…”

Development of live-attenuated arenavirus vaccines based on codon deoptimization of the viral glycoprotein

“…The small (S) segment encodes for the viral glycoprotein precursor (GPC) and the viral nucleoprotein (NP). GPC is co-translationally cleaved by signal peptidase to produce a stable 58 amino acid Stable Signal Peptide (SSP) and GPC that is post-translationally processed by the cellular Site 1 Protease (S1P) to yield the two mature virion GP1 and GP2 glycoproteins that together with SSP form the GP complex involved in receptor binding and virus cell entry (Beyer et al, 2003; Buchmeier et al, 2007; Pinschewer et al, 2003; Rojek and Kunz, 2008; Rojek et al, 2008), NP, is the most abundant viral protein in infected cells and virions (Buchmeier et al, 2007) and performs multiple roles during infection, including encapsidation of the viral genome RNA species to form, together with L, the viral ribonucleoprotein (vRNPs) complex that directs the biosynthetic processes of RNA replication and gene transcription of the viral genome (Lee et al, 2000; Ortiz-Riano et al, 2012a, 2012b), and inhibition of the cellular type I interferon (IFN-I) (Borrow et al, 2010; Martinez-Sobrido et al, 2006, 2007, 2009, Pythoud et al, 2012, 2015) and inflammatory (Borrow et al, 2010; Lee et al, 2000; Rodrigo et al, 2012) responses.…”

Novel Functions of IFI44L as a Feedback Regulator of Host Antiviral Responses

“…genome, is recognized by TLR-3 (double-stranded RNA [dsRNA]), TLR-7 and TLR-8 (ssRNA), RIG-I (5= triphosphate ssRNA), and NLRP3 (5). Lymphocytic choriomeningitis virus (LCMV), the prototype member of the Arenaviridae family, which contains a negative-sense genome comprised of two ssRNA viral segments, is mainly recognized by TLR-7, RIG-I, and melanoma differentiation-associated gene 5 (MDA-5) (6). Coronaviruses (CoVs) are positive-sense ssRNA viruses recognized by MDA-5, TLR-7, and RIG-I (7)(8)(9).…”