Hijacking of the Early Endosomal Pathway by novel tick-borne bunyavirus

University Of Texas Med Br Galveston, Galveston TX

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Abstract

? DESCRIPTION (provided by applicant): Severe Fever with Thrombocytopenia Syndrome virus (SFTSV) is a newly recognized member of the family Bunyaviridae, genus Phlebovirus. The virus was isolated from patients presenting with hemorrhagic manifestations and an initial case fatality rate of 12-30% was reported. Knowledge concerning exploitation of cellular processes by SFTSV is currently limited. Additionally, no vaccines or therapeutics are available against SFTSV. Recently, we reported that the nonstructural NSs protein of SFTSV is a potent inhibitor of interferon (IFN) responses. We also found that SFTSV NSs relocalizes key components of the IFN pathway into SFTSV NSs-positive cytoplasmic structures and that these structures co-localize with the early endosomal marker Rab5 but not with Golgi or endoplasmic reticulum markers. Furthermore, we have found that the viral RNP complex and nascent viral RNA are harbored within these structures. In this study, we will use electron and confocal microscopy, protein interaction assays, and live cell imaging to investigate the source (Aim 1) and role (Aim 2) these structures play during SFTSV infection, and determine the mechanism by which components of the innate immune response are targeted into these structures (Aim 3). The outcome of this research will provide valuable insights into two novel and distinct mechanisms used for viral replication and innate immune evasion by SFTSV. This knowledge will be vital to the rational development of effective countermeasures against SFTSV and other newly emergent bunyaviruses.