Junín Virus Infection Activates the Type I Interferon Pathway in a RIG-I-Dependent Manner

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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

“…9). This appears distinct from the effects of JUNV and other RNA viruses, like VSV and SeV, that induce both IFN-I and apoptosis via RIG-I/MAVS (28,35).…”

Section: Discussionmentioning

confidence: 70%

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confidence: 99%

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

Pythoud

Rothenberger

Martínez-Sobrido

et al. 2015

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“…Following the rescue and single passage in Vero cells, the rMACV-F438I titer was 4 ϫ 10 7 PFU/ml, comparable to those of MACV and rMACV (23,36,40). Sequencing of the stock virus confirmed the presence of the single mutation at nt 1400 along with two silent genetic markers at nt 808 and nt 1447 on the S segment: the first allows us to distinguish all recombinant viruses from MACV, and the second distinguishes rMACV-F438I from rMACV ( Fig.…”

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confidence: 78%

A Substitution in the Transmembrane Region of the Glycoprotein Leads to an Unstable Attenuation of Machupo Virus

Patterson

Koma

Seregin

et al. 2014

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Machupo virus (MACV) is the etiologic agent of Bolivian hemorrhagic fever (BHF). Utilizing a reverse-genetics system recently developed, we report the rescue of a rationally modified recombinant MACV containing a single mutation in the transmembrane region of the glycoprotein. Following challenge of susceptible mice, we identified a significant reduction in virulence in the novel virus. We also identified an instability leading to reversion of the single mutation to a wild-type genotype.

“…Our work and that of others have shown that cytoplasmic viral genomic RNA is recognized initially by the cytoplasmic retinoic acid-inducible gene I (RIG-I) and later by the endosomal Toll-like receptor 3 (TLR3) (17,18), whose coordinated actions are required for an effective innate immune response (19)(20)(21). Upon binding to RSV or 5= triphosphorylated RNAs, RIG-I undergoes a conformational switch via inducible K63-linked polyubiquitylation (22,23).…”

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confidence: 80%

Ataxia Telangiectasia Mutated Kinase Mediates NF-κB Serine 276 Phosphorylation and Interferon Expression via the IRF7-RIG-I Amplification Loop in Paramyxovirus Infection

Fang

Choudhary

Tian

et al. 2015

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Respiratory syncytial virus (RSV) is Respiratory syncytial virus (RSV), a negative-sense, singlestranded RNA (ssRNA) virus of the Paramyxoviridae family, is one of the most important respiratory pathogens of young children worldwide (1). Epidemiological studies have shown that RSV infects almost all children in the United States by the age of 3, producing primarily upper respiratory tract infections and otitis media (2). In a small subset of immunologically naive or predisposed infants, RSV infection produces a more severe, lower respiratory tract infection (LRTI), an event that accounts for over 3 million hospitalizations and about 200,000 deaths (3, 4). Importantly, there are no effective vaccines or treatments available (2).In seasonal epidemics, RSV is spread via large droplets and self-inoculation (3). Once infected, RSV replicates in the nasal mucosa intraepithelial bridges into the lower respiratory tract or by free virus in respiratory secretions binding to epithelial cilia (5, 6). In the lower airway, RSV replicates primarily in epithelial cells, where it generates bronchial inflammation, epithelial necrosis, sloughing, peribronchial mononuclear cell infiltration, and submucosal edema producing obstructive physiology (7-9). The pathogenesis of LRTI involves an interplay between viral inoculum, host factors, and immune response and is not fully understood (10). Children with bronchiolitis present symptoms at times