The Pathogenesis of Severe Fever with Thrombocytopenia Syndrome Virus Infection in Alpha/Beta Interferon Knockout Mice: Insights into the Pathologic Mechanisms of a New Viral Hemorrhagic Fever

Abstract

Severe fever with thrombocytopenia syndrome virus (SFTSV) is a newly discovered Phlebovirus causing an emerging hemorrhagic fever in East Asia, with reported case fatality rates up to 30%. Despite the high case fatality rate and large number of persons at risk of infection, the pathobiology of the disease is unknown, and no effective animal model has been available for investigating its pathogenesis. We have studied mice and hamsters as potential small-animal models of SFTSV infection following subcutaneous, intraperitoneal, or intracerebral inoculation. Animal tissues were processed for viral load determination, histopathology, immunohistochemistry, and confocal microscopic studies. We found that immunocompetent adult mice and hamsters did not become ill after SFTSV infection. However, alpha/beta interferon receptor knockout (IFNAR ؊/؊ ) mice were highly susceptible to SFTSV infection, and all mice died within 3 to 4 days after subcutaneous inoculation of 10 6 focus-forming units of SFTSV. Histologic examination of tissues of IFNAR ؊/؊ mice infected with SFTSV showed no detectable lesions. In contrast, by immunohistochemistry virus antigen was found in liver, intestine, kidney, spleen, lymphoid tissue, and brain, but not in the lungs. Mesenteric lymph nodes and spleen were the most heavily infected tissues. Quantitative reverse transcription-PCR (RT-PCR) confirmed the presence of virus in these tissues. Confocal microscopy showed that SFTSV colocalized with reticular cells but did not colocalize with dendritic cells, monocytes/macrophages, neutrophils, or endothelium. Our results indicate that SFTSV multiplied in all organs except for lungs and that mesenteric lymph nodes and spleen were the most heavily infected tissues. The major target cells of SFTSV appear to be reticular cells in lymphoid tissues of intestine and spleen.

Modeling Severe Fever with Thrombocytopenia Syndrome Virus Infection in Golden Syrian Hamsters: Importance of STAT2 in Preventing Disease and Effective Treatment with Favipiravir

“…In contrast, we did not observe lymphoid necrosis in the lymph nodes evaluated. Interestingly, the report by Liu and colleagues using IFNAR Ϫ/Ϫ mice on a different background (129/Sv) and with a different strain of SFTSV (YL-1) detected SFTSV by immunohistochemistry in multiple organs, but no histologic lesions were present (10). Collectively, the results from rodent studies support the idea that type I IFN is essential but that host and virus factors, as well as challenge dose and route, can alter disease development.…”

“…Immunocompetent mice and golden Syrian hamsters have been shown to be refractory to severe infection and disease following SFTSV challenge; however, mice lacking IFN-␣/␤ receptors are highly susceptible and generally succumb from an acute disease course (9)(10)(11). In the present study, we demonstrate an essential role for STAT2 in the control of SFTSV infection in hamsters and subsequently characterize the pathogenesis and natural history of disease in hamsters deficient in STAT2 signaling.…”

“…Wild-type Syrian hamsters are refractory to disease following SFTSV challenge (10). To investigate whether STAT2 deficiency would render hamsters susceptible to SFTSV, STAT2 KO hamsters were inoculated subcutaneously (s.c.) with serial dilutions of SFTSV (10, 1, or 0.1 PFU) or sham infected and observed for signs of illness.…”

“…Previous SFTSV studies in mice have demonstrated the importance of the type I IFN response in preventing severe disease in mice (10). Further, recent studies using human cells have shown that STAT2 is specifically targeted and sequestered by the NSs protein of SFTSV during infection as a mechanism for blocking the initiation of the type I IFN response program (5).…”

Immunization with Recombinant SFTSV/NSs Protein Does Not Promote Virus Clearance in SFTSV-Infected C57BL/6J Mice

“…Virus propagation was carried out with Vero E6 cells cultured in RPMI 1640 medium containing 10% fetal calf serum (Gibco) (7). Virus titer was determined by a focus forming assay on Vero E6 cells (12). SFTSV RNA genome was isolated from SFTSV virus stocks using the TIANamp Virus DNA/RNA Kit [Tiangen Biotech (Beijing) Co., Ltd.] according to the manufacturer's instructions.…”