The novel bunyavirus Severe Fever Thrombocytopenia Syndrome virus (SFTSV) was recently isolated from patients presenting with fever, thrombocytopenia and hemorrhagic manifestations. An initial case fatality rate of 12-30% has been reported and evidence of person-to-person transmission has also been recently documented. The exact mechanism by which this virus causes disease is still unknown. The possibility of person-to-person transmission, the high fatality rate associated with infection and the recent emergence of Heartland virus, a close relative of SFTSV, highlights the need to increase our knowledge on how these new pathogens cause diseases. Furthermore, it also underscores the need to develop therapeutic interventions against these emerging pathogens. We have determined that the SFTSV nonstructural NSs protein is a potent inhibitor of host interferon (IFN) responses. Astonishingly, we found that the SFTSV nonstructural NSs protein interacts with and relocalizes RIG-I, TRIM25 and TBK1, key components of the Type I IFN response pathway, into NSs-induced cytoplasmic structures in a process that involves ubiquitin and the early endosome pathway. Thus, the goal of this project is to provide a detailed understanding of how these cellular processes are targeted by SFTSV to counteract host innate immune responses and establish infection. Completion of this study will describe a novel immune evasion strategy for subversion of host innate immunity by SFTSV that is distinct from the current paradigm for bunyaviruses. We expect the fundamental information generated in this project will advance the field by defining a novel immune evasion strategy for subversion of host innate immune responses and very likely provide new targets for therapeutic interventions and vaccine development against SFTSV and other related pathogenic RNA viruses.
Severe Fever with Thrombocytopenia Syndrome (SFTS) is a hemorrhagic fever disease caused by the novel tick-borne phlebovirus Severe Fever with Thrombocytopenia Syndrome (SFTSV), which is found in Asia and is closely related to Heartland virus found in the US. This project will investigate SFTSV-mediated antagonism of the host innate immune response and elucidate the role of protein ubiquitnation and the endosomal pathway in the evasion of host responses by SFTSV. The finding will lead to an increased understanding of the pathogenesis of SFTS and the future development of antiviral strategies for this important pathogen.
| Silvas, Jesus A; Aguilar, Patricia V (2017) The Emergence of Severe Fever with Thrombocytopenia Syndrome Virus. Am J Trop Med Hyg 97:992-996 |
| Klionsky, Daniel J (see original citation for additional authors) (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222 |
| Silvas, Jesus A; Popov, Vsevolod L; Paulucci-Holthauzen, Adriana et al. (2016) Extracellular Vesicles Mediate Receptor-Independent Transmission of Novel Tick-Borne Bunyavirus. J Virol 90:873-86 |
