The Andes Orthohantavirus NSs Protein Antagonizes the Type I Interferon Response by Inhibiting MAVS Signaling

Abstract

The small messenger RNA (SmRNA) of the Andes orthohantavirus (ANDV), a rodent-borne member of the Hantaviridae family of viruses of the Bunyavirales order, encodes a multifunctional nucleocapsid (N) protein and for a nonstructural (NSs) protein of unknown function. We have previously shown the expression of the ANDV-NSs, but only in infected cell cultures. In this study, we extend our early findings by confirming the expression of the ANDV-NSs protein in the lungs of experimentally infected golden Syrian hamsters. Next, we show, using a virus-free system, that the ANDV-NSs protein antagonizes the type I interferon (IFN) induction pathway by suppressing signals downstream of the melanoma differentiation-associated protein 5 (MDA5) and the retinoic acid-inducible gene 1 (RIG-I) and upstream of TBK1. Consistent with this observation, the ANDV-NSs protein antagonized mitochondrial antiviral-signaling protein (MAVS)-induced IFN-β, NF-κB, IFN-regulatory factor 3 (IRF3), and IFN-sensitive response element (ISRE) promoter activity. Results demonstrate that ANDV-NSs binds to MAVS in cells without disrupting the MAVS-TBK-1 interaction. However, in the presence of the ANDV-NSs ubiquitination of MAVS is reduced. In summary, this study provides evidence showing that the ANDV-NSs protein acts as an antagonist of the cellular innate immune system by suppressing MAVS downstream signaling by a yet not fully understand mechanism. Our findings reveal new insights into the molecular regulation of the hosts’ innate immune response by the Andes orthohantavirus. IMPORTANCE Andes orthohantavirus (ANDV) is endemic in Argentina and Chile and is the primary etiological agent of hantavirus cardiopulmonary syndrome (HCPS) in South America. ANDV is distinguished from other hantaviruses by its unique ability to spread from person to person. In a previous report, we identified a novel ANDV protein, ANDV-NSs. Until now, ANDV-NSs had no known function. In this new study, we established that ANDV-NSs acts as an antagonist of cellular innate immunity, the first line of defense against invading pathogens, hindering the cellular antiviral response during infection. This study provides novel insights into the mechanisms used by ANDV to establish its infection.

Interactions of Viral Proteins from Pathogenic and Low or Non-Pathogenic Orthohantaviruses with Human Type I Interferon Signaling

“…Only a few studies have suggested a role of hantaviral NSs in IFN antiviral response [ 21 ]. A recent study described the detection of ANDV NSs in lungs of infected Syrian hamsters used as model of pathogenesis, and it has shown that ANDV NSs antagonizes the IFN-I signaling pathway by disrupting MAVS-TBK1 interaction [ 60 ]. It has been published that PUUV deficient for NSs expression was 10 times less infectious in A549 interferon competent cells than the wild-type virus strain [ 7 ].…”

Broadly Antiviral Activities of TAP1 through Activating the TBK1-IRF3-Mediated Type I Interferon Production

“…Subsequently, Type I IFNs can bind to IFNAR2, and then recruit IFNAR1, and consequently form a signaling-competent ternary complex to activate the heterotrimeric transcription factor complex interferon-stimulated gene factor 3 (ISGF3), which is comprised of phosphorylated signal transducer and activator of transcription (STAT)1 and STAT2 and interferon regulatory factor 9 (IRF9), through the Janus kinase (JAK)-STAT signal pathway [ 31 , 32 , 33 ]. The activated ISGF3 can translocate to the nucleus and bind to IFN-stimulated response elements (ISREs) in the upstream promoter regions of ISGs [ 34 , 35 ] and then encode the numerous proteins with potent antiviral activities [ 18 , 36 ].…”

Immune response during hantavirus diseases: implications for immunotherapies and vaccine design

“…9 Upon viral infection, pathogen-associated molecular patterns are recognized by host cell receptors at extra-and intracellular levels as Toll-like receptors (TLR), retinoic acid-inducible gene I (RIG-I), melanoma differentiation-associated protein 5 (MDA5) and protein kinases (PKR). [69][70][71][72][73][74][75][76] TLR3 recognizes the double-stranded RNA (dsRNA) viral replication intermediate, promoting the synthesis of alpha/beta interferon (IFN-a/b) and interferon-stimulated genes (ISGs) to fight the viral infection. 69 Nevertheless, pathogenic hantaviruses apparently alter the activation of TLR3 and its downstream effectors.…”