Infection Of Humanized Mice With A Novel Phlebovirus Presented Pathogenic Features Of Sever Fever With Thrombocytopenia Syndrome

Severe fever with thrombocytopenia syndrome virus (SFTSV) is a tick-borne emerging phlebovirus with high mortality rates of 6.0 to 30%. SFTSV infection is characterized by high fever, thrombocytopenia, leukopenia, hemorrhage and multiple organ failures. Currently, specific therapies and vaccines remain elusive. Suitable small animal models are urgently needed to elucidate the pathogenesis and evaluate the potential drug and vaccine for SFTSV infection. Previous models presented only mild or no pathogenesis of SFTS, limiting their applications in SFTSV infection. Therefore, it is an urgent need to develop a small animal model for the investigation of SFTSV pathogenesis and evaluation of therapeutics. In the current report, we developed a SFTSV infection model based on the HuPBL-NCG mice that recapitulates many pathological characteristics of SFTSV infection in humans. Virus-induced histopathological changes were identified in spleen, lung, kidney, and liver. SFTSV was colocalized with macrophages in the spleen and liver, suggesting that the macrophages in the spleen and liver could be the principle target cells of SFTSV. In addition, histological analysis showed that the vascular endothelium integrity was severely disrupted upon viral infection along with depletion of platelets. In vitro cellular assays further revealed that SFTSV infection increased the vascular permeability of endothelial cells by promoting tyrosine phosphorylation and internalization of the adhesion molecule vascular endothelial (VE)-cadherin, a critical component of endothelial integrity. In addition, we found that both virus infection and pathogen-induced exuberant cytokine release dramatically contributed to the vascular endothelial injury. We elucidated the pathogenic mechanisms of hemorrhage syndrome and developed a humanized mouse model for SFTSV infection, which should be helpful for anti-SFTSV therapy and pathogenesis study.Author summary SFTSV is a novel bunyavirus that was identified in 2010 and endemic in China, Korea, Japan and Vietnam with expanding spatial incidents. SFTS is characterized by high case-fatality rates and currently has no effective therapeutics or vaccines. In previous study, models presented only mild or no pathogenesis of SFTS, limiting their applications in SFTSV infection. In the current study, we developed a humanized NCG mouse model for the study of SFTSV infection and elucidated the pathogenic mechanisms of hemorrhage syndrome with respect to apoptosis, membrane protein endocytosis and cytokine stimulation. The HuPBL-NCG model presented multiple organ pathologies that resemble those of human infection, which will be helpful for anti-SFTSV therapy and pathogenesis study.