Pathogenicity of severe fever with thrombocytopenia syndrome virus in mice regulated in type I interferon signaling

Abstract

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging zoonotic disease, which causes high fever, thrombocytopenia, and death in humans and animals in East Asian countries. The pathogenicity of SFTS virus (SFTSV) remains unclear. We intraperitoneally infected three groups of mice: wild-type (WT), mice treated with blocking anti-type I interferon (IFN)-α receptor antibody (IFNAR Ab), and IFNAR knockout (IFNAR−/−) mice, with four doses of SFTSV (KH1, 5 × 105 to 5 × 102 FAID50). The WT mice survived all SFTSV infective doses. The IFNAR Ab mice died within 7 days post-infection (dpi) with all doses of SFTSV except that the mice were infected with 5 × 102 FAID50 SFTSV. The IFNAR−/− mice died after infection with all doses of SFTSV within four dpi. No SFTSV infection caused hyperthermia in any mice, whereas all the dead mice showed hypothermia and weight loss. In the WT mice, SFTSV RNA was detected in the eyes, oral swabs, urine, and feces at 5 dpi. Similar patterns were observed in the IFNAR Ab and IFNAR−/− mice after 3 dpi, but not in feces. The IFNAR Ab mice showed viral shedding until 7 dpi. The SFTSV RNA loads were higher in organs of the IFNAR−/− mice compared to the other groups. Histopathologically, coagulation necrosis and mononuclear inflammatory cell infiltration in the liver and white pulp atrophy in the spleen were seen as the main lesions in the IFN signaling lacking mice. Immunohistochemically, SFTSV antigens were mainly detected in the marginal zone of the white pulp of the spleen in all groups of mice, but more viral antigens were observed in the spleen of the IFNAR−/− mice. Collectively, the IFN signaling-deficient mice were highly susceptible to SFTSV and more viral burden could be demonstrated in various excreta and organs of the mice when IFN signaling was inhibited.

Animal Model of Severe Fever With Thrombocytopenia Syndrome Virus Infection

“…To overcome the host restriction of SFTSV pathogenicity, immunocompromised adult mice including IFN-α/β receptor knockout ( Ifnar –/– ) or STAT2 knockout ( Stat2 –/– ) mice and those treated with blocking antibody against IFNAR (IFNAR Ab) or mitomycin C have been used for SFTSV infection. As expected, these animals were indeed demonstrated to be relatively susceptible to SFTSV challenge and displayed some severe clinical manifestations of human infection ( Figure 1 and Table 1 ; Chen et al, 2012 ; Jin et al, 2012 ; Liu Y. et al, 2014 ; Matsuno et al, 2017 ; Westover et al, 2019 ; Yoshikawa et al, 2019 ; Park et al, 2020 ; Perez-Sautu et al, 2020 ).…”

“…Histopathologically, the IFNAR Ab mice with SFTSV infection developed significant but self-restorative lesions including coagulation necrosis and mononuclear inflammatory infiltration in liver, white pulp atrophy of spleen, and injury of intestinal villi at day 7 p.i. However, these lesions seemed milder than those in the Ifnar −/− mice (Park et al, 2020). Together, the sensitivity of IFNAR Ab mice appears to be intermediate between WT and Ifnar −/− mice and these IFNAR Ab-treated animals might be used as an alternative model to make up for the deficiency of Ifnar −/− mouse.…”

“…In these following studies, Ifnar −/− mice infected with SFTSV exhibited remarkable hematologic changes like severe viremia and leukocytopenia, developed clinical manifestations such as severe weight loss, ruffled fur, and depression, and succumbed to the infection (Tani et al, 2016;Matsuno et al, 2017;Westover et al, 2019;Park et al, 2020). Significant histopathological abnormalities of spleen, liver, kidney, lymph nodes, and bone marrow were common, among which spleen was likely the major target organ with the highest virus titers (Tani et al, 2016;Matsuno et al, 2017;Westover et al, 2019;Park et al, 2020). Lesions of spleen predominantly consisted of histiocytic and necrotizing splenitis, white pulp atrophy, and diffuse reticuloendothelial hyperplasia of red pulp (Tani et al, 2016;Matsuno et al, 2017;Park et al, 2020).…”

“…and thrombocytopenia at day 3 p.i., showing an increase of ALT, AST and BUN, and shedding SFTSV via various excreta. All survived and clinical symptoms such as fever and body weight loss were not observed ( Jin et al, 2012 ; Park et al, 2020 ). Viral replication was only detected in the spleen, indicating that spleen might be the target organ of SFTSV in the model ( Jin et al, 2012 ).…”

Vaccine Development for Severe Fever with Thrombocytopenia Syndrome

“…However, they develop hallmark symptoms of thrombocytopenia and leukocytopenia with transient viral replication in the spleen [32,33]. In contrast, two mouse strains on the C57BL/6 background are highly susceptible to SFTSV infection [33][34][35][36]. The mouse strains are deficient of the type I interferon receptor-deficient (Ifnar −/− ) or signal transducer and activator of transcription 2-deficient (Stat2 −/− ) genes, which are essential for the innate immune signaling pathway.…”