Molecular Mechanism Of Host Responses Regulated By Nonstructural Protein NSs In Heartland Virus Infected

Heartland Virus(HLV)is a novel tick-borne bunyavirus identified since 2009 in the United States.After the onset of illnessthe patients experienced fever,fatigue,headache,muscle pain,joint pain,anorexia,diarrhea and other symptoms and suffered from neutropenia,lymphopenia,and thrombocytopenia.Severe fever with thrombocytopenia syndrome(SFTS)is an emerging infectious disease found in China since 2007,which is also a tick-borne viral disease casued by SFTS bunyavirus(SFTSV).The symptoms of SFTS are more severe,the mortality rate once reached 15%or highter and had raised great concern in public health.HLV and SFTSV belong to the genus Phlebovirus of Bunyaviridae Progresses have been.made in recent years on the studies on the pathogenesis,virus-host interaction,and host responses of SFTSV.Previous studies have observed that the nonstructural protein NSs of SFTSV had an inhibitory effect on innate immunity through its interaction with TBK1 kinase,important in interferon signaling pathway.NSs could translocate TBK1,IKK ε as well as IRF3 into viral inclusion bodies,formed by NSs,thus blocking the translocation of IRF3 into the nucleus to activate the induction of interferon β and thus promote viral proliferation.HLV is the closest virus to the SFTSV in structure,and the identities of viral NP and NSs between the two viruses ranged from 65 to70%,while their homology to other members of the genus is less than 35%.Up to now little has been known about HLV,its pathogenesis,and its interaction with host cells.The aim of this study is to examine the effect of HLV on host responses and innate immunity,and the mechanism by which the NSs of HLV interacts with host proteins.The specific goals of this study include:First,to explore the effect of NSs on host cell responses and virus proliferation;Second,to study the mechanism of NSs regulating innate immunity by interaction with TBK1 and other components important in interferon signaling pathway.Our study show that HLV NSs inhibited host cell by IFNb induction in transfected and infected cells,similar to NSs of SFTSV.NSs from both HLV and SFTSV could inhibit phosphorylation of IRF3,however,NSs of SFTSV differs from that of HLV in that HLV NSs did not form the characteristic inclusion body structures in transfected and infected cells.Although HLV NSs inhibits phosphorylation of IRF3 its interaction with TBK1 did not affect the binding of TBK1 with IRF3,unlike SFTSV NSs.Apparently NSs from HLV and SFTSV has a significant difference in their mechanism in inhibition of IFN induction.This study will enhance our current understanding of the newly found tick-borne bunyaviruses in their interactions with host and viral pathogenesis in humans.