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

Giulia Gallo,Noël Tordo,Ana Da Silva Filipe,Samuel Terrier,Florian Binder,Karine Badonnel,Rainer G Ulrich,Guillaume Chevreux,Myriam Ermonval,Grégory Caignard,Quan Gu,Agnieszka Szemiel,Damien Vitour,Alain Kohl,Gleyder Roman-Sosa

doi:10.3390/v13010140

Abstract

Rodent-borne orthohantaviruses are asymptomatic in their natural reservoir, but they can cause severe diseases in humans. Although an exacerbated immune response relates to hantaviral pathologies, orthohantaviruses have to antagonize the antiviral interferon (IFN) response to successfully propagate in infected cells. We studied interactions of structural and nonstructural (NSs) proteins of pathogenic Puumala (PUUV), low-pathogenic Tula (TULV), and non-pathogenic Prospect Hill (PHV) viruses, with human type I and III IFN (IFN-I and IFN-III) pathways. The NSs proteins of all three viruses inhibited the RIG-I-activated IFNβ promoter, while only the glycoprotein precursor (GPC) of PUUV, or its cleavage product Gn/Gc, and the nucleocapsid (N) of TULV inhibited it. Moreover, the GPC of both PUUV and TULV antagonized the promoter of IFN-stimulated responsive elements (ISRE). Different viral proteins could thus contribute to inhibition of IFNβ response in a viral context. While PUUV and TULV strains replicated similarly, whether expressing entire or truncated NSs proteins, only PUUV encoding a wild type NSs protein led to late IFN expression and activation of IFN-stimulated genes (ISG). This, together with the identification of particular domains of NSs proteins and different biological processes that are associated with cellular proteins in complex with NSs proteins, suggested that the activation of IFN-I is probably not the only antiviral pathway to be counteracted by orthohantaviruses and that NSs proteins could have multiple inhibitory functions.

Highlights

Orthohantaviruses belong to the Bunyavirales order, according to International Committee on taxonomy of viruses (ICTV) taxon classification update
As other negative stranded RNA viruses, orthohantaviruses are recognized by RIGI/MDA5 receptors triggering the production of IFN [34]
HEK293T cells transfected with plasmid constructs expressing viral proteins N, NSs, or the cytosolic tails of Gn under different forms allowing for intracellular membrane insertion and cytosolic localization, which could lead to different topological organization, i.e., GnCT, TM1-GnCT, and GnCT-TM2 all fused in frame with a 3xFlag tag at their N-ter (Figure 1a)

Summary

Introduction

Orthohantaviruses (family Hantaviridae, subfamily Mammantavirinae, genus Orthohantavirus) belong to the Bunyavirales order, according to International Committee on taxonomy of viruses (ICTV) taxon classification update (https://talk.ictvonline.org/taxonomy/). In contrast to most of the viruses in the order, orthohantaviruses are not arboviruses and they are hosted by rodents and small insectivorous mammals (moles, shrews) They have co-evolved for thousands of years with their animal reservoir and exhibit exquisite natural host specificity with these natural hosts [1,2]. Along with their reservoir, rodent-borne orthohantaviruses are distributed all over the world and some of them are responsible for disease clusters or outbreaks, which makes these emerging and re-emerging viruses of great public health concern [3]. Orthohantaviruses interact with the innate immune system by exacerbating the innate response at the level of targeted organs, while, on the other hand, they must counteract the IFN antiviral pathway [6,7]

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