Differential antagonism of human innate immune responses by tick-borne Phlebovirus nonstructural proteins

Rezelj, V. V., Li, P. , Chaudhary, V., Elliott, R. M., Jin, D.-Y. and Brennan, B. (2017) Differential antagonism of human innate immune responses by tick-borne Phlebovirus nonstructural proteins. mSphere, 2(3), e00234-17. (doi: 10.1128/mSphere.00234-17) (PMID:28680969) (PMCID:PMC5489658)

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In recent years, several newly discovered tick-borne viruses causing a wide spectrum of diseases in humans have been ascribed to the Phlebovirus genus of the Bunyaviridae family. The nonstructural protein (NSs) of bunyaviruses is the main virulence factor and interferon (IFN) antagonist. We studied the molecular mechanisms of IFN antagonism employed by the NSs proteins of human apathogenic Uukuniemi virus (UUKV) and those of Heartland virus (HRTV) and severe fever with thrombocytopenia syndrome virus (SFTSV), both of which cause severe disease. Using reporter assays, we found that UUKV NSs weakly inhibited the activation of the beta interferon (IFN-β) promoter and response elements. UUKV NSs weakly antagonized human IFN-β promoter activation through a novel interaction with mitochondrial antiviral-signaling protein (MAVS), confirmed by coimmunoprecipitation and confocal microscopy studies. HRTV NSs efficiently antagonized both IFN-β promoter activation and type I IFN signaling pathways through interactions with TBK1, preventing its phosphorylation. HRTV NSs exhibited diffused cytoplasmic localization. This is in comparison to the inclusion bodies formed by SFTSV NSs. HRTV NSs also efficiently interacted with STAT2 and impaired IFN-β-induced phosphorylation but did not affect STAT1 or its translocation to the nucleus. Our results suggest that a weak interaction between STAT1 and HRTV or SFTSV NSs may explain their inability to block type II IFN signaling efficiently, thus enabling the activation of proinflammatory responses that lead to severe disease. Our findings offer insights into how pathogenicity may be linked to the capacity of NSs proteins to block the innate immune system and illustrate the plethora of viral immune evasion strategies utilized by emerging phleboviruses.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Elliott, Professor Richard and Brennan, Dr Benjamin and Li, Dr Ping and Rezelj, Veronica Valentina
Authors: Rezelj, V. V., Li, P., Chaudhary, V., Elliott, R. M., Jin, D.-Y., and Brennan, B.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:mSphere
Publisher:American Society for Microbiology
ISSN (Online):2379-5042
Published Online:28 June 2017
Copyright Holders:Copyright © 2017 Rezelj et al.
First Published:First published in mSphere 2(3):e00234-17
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
635361Molecular analyses of arbovirus-host interactionsMassimo PalmariniWellcome Trust (WELLCOTR)099220/B/12/ZMVLS III - CENTRE FOR VIRUS RESEARCH