Differential Antagonism of Human Innate Immune Responses by Tick-Borne <italic toggle="yes">Phlebovirus</italic> Nonstructural Proteins

ABSTRACT 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...

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Autores principales:	Veronica V. Rezelj, Ping Li, Vidyanath Chaudhary, Richard M. Elliott, Dong-Yan Jin, Benjamin Brennan
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	emerging pathogens nonstructural protein phlebovirus bunyavirus innate immunity Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/28fcefcd73974461b389b4d73ec685c9
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spelling	oai:doaj.org-article:28fcefcd73974461b389b4d73ec685c92021-11-15T15:21:46ZDifferential Antagonism of Human Innate Immune Responses by Tick-Borne <italic toggle="yes">Phlebovirus</italic> Nonstructural Proteins10.1128/mSphere.00234-172379-5042https://doaj.org/article/28fcefcd73974461b389b4d73ec685c92017-06-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00234-17https://doaj.org/toc/2379-5042ABSTRACT 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. IMPORTANCE Since 2011, there has been a large expansion in the number of emerging tick-borne viruses that have been assigned to the Phlebovirus genus. Heartland virus (HRTV) and SFTS virus (SFTSV) were found to cause severe disease in humans, unlike other documented tick-borne phleboviruses such as Uukuniemi virus (UUKV). Phleboviruses encode nonstructural proteins (NSs) that enable them to counteract the human innate antiviral defenses. We assessed how these proteins interacted with the innate immune system. We found that UUKV NSs engaged with innate immune factors only weakly, at one early step. However, the viruses that cause more severe disease efficiently disabled the antiviral response by targeting multiple components at several stages across the innate immune induction and signaling pathways. Our results suggest a correlation between the efficiency of the virus protein/host interaction and severity of disease.Veronica V. RezeljPing LiVidyanath ChaudharyRichard M. ElliottDong-Yan JinBenjamin BrennanAmerican Society for Microbiologyarticleemerging pathogensnonstructural proteinphlebovirusbunyavirusinnate immunityMicrobiologyQR1-502ENmSphere, Vol 2, Iss 3 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	emerging pathogens nonstructural protein phlebovirus bunyavirus innate immunity Microbiology QR1-502
spellingShingle	emerging pathogens nonstructural protein phlebovirus bunyavirus innate immunity Microbiology QR1-502 Veronica V. Rezelj Ping Li Vidyanath Chaudhary Richard M. Elliott Dong-Yan Jin Benjamin Brennan Differential Antagonism of Human Innate Immune Responses by Tick-Borne <italic toggle="yes">Phlebovirus</italic> Nonstructural Proteins
description	ABSTRACT 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. IMPORTANCE Since 2011, there has been a large expansion in the number of emerging tick-borne viruses that have been assigned to the Phlebovirus genus. Heartland virus (HRTV) and SFTS virus (SFTSV) were found to cause severe disease in humans, unlike other documented tick-borne phleboviruses such as Uukuniemi virus (UUKV). Phleboviruses encode nonstructural proteins (NSs) that enable them to counteract the human innate antiviral defenses. We assessed how these proteins interacted with the innate immune system. We found that UUKV NSs engaged with innate immune factors only weakly, at one early step. However, the viruses that cause more severe disease efficiently disabled the antiviral response by targeting multiple components at several stages across the innate immune induction and signaling pathways. Our results suggest a correlation between the efficiency of the virus protein/host interaction and severity of disease.
format	article
author	Veronica V. Rezelj Ping Li Vidyanath Chaudhary Richard M. Elliott Dong-Yan Jin Benjamin Brennan
author_facet	Veronica V. Rezelj Ping Li Vidyanath Chaudhary Richard M. Elliott Dong-Yan Jin Benjamin Brennan
author_sort	Veronica V. Rezelj
title	Differential Antagonism of Human Innate Immune Responses by Tick-Borne <italic toggle="yes">Phlebovirus</italic> Nonstructural Proteins
title_short	Differential Antagonism of Human Innate Immune Responses by Tick-Borne <italic toggle="yes">Phlebovirus</italic> Nonstructural Proteins
title_full	Differential Antagonism of Human Innate Immune Responses by Tick-Borne <italic toggle="yes">Phlebovirus</italic> Nonstructural Proteins
title_fullStr	Differential Antagonism of Human Innate Immune Responses by Tick-Borne <italic toggle="yes">Phlebovirus</italic> Nonstructural Proteins
title_full_unstemmed	Differential Antagonism of Human Innate Immune Responses by Tick-Borne <italic toggle="yes">Phlebovirus</italic> Nonstructural Proteins
title_sort	differential antagonism of human innate immune responses by tick-borne <italic toggle="yes">phlebovirus</italic> nonstructural proteins
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/28fcefcd73974461b389b4d73ec685c9
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Differential Antagonism of Human Innate Immune Responses by Tick-Borne <italic toggle="yes">Phlebovirus</italic> Nonstructural Proteins

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