Vascular Leak and Hypercytokinemia Associated with Severe Fever with Thrombocytopenia Syndrome Virus Infection in Mice

Abstract

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging viral hemorrhagic fever (VHF) endemic to China, South Korea, Japan, and Vietnam. Here we characterize the pathogenesis and natural history of disease in IFNAR-/- mice challenged with the HB29 strain of SFTS virus (SFTSV) and demonstrate hallmark features of VHF such as vascular leak and high concentrations of proinflammatory cytokines in blood and tissues. Treatment with FX06, a natural plasmin digest product of fibrin in clinical development as a treatment for vascular leak, reduced vascular permeability associated with SFTSV infection but did not significantly improve survival outcome. Further studies are needed to assess the role of vascular compromise in the SFTS disease process modeled in IFNAR-/- mice.

Animal Model of Severe Fever With Thrombocytopenia Syndrome Virus Infection

“…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). In addition, similar to human severe cases, Westover et al (2019) reported SFTSV-induced vascular fibrinoid necrosis in spleen in Ifnar −/− mice, which was accompanied by increased pro-inflammatory cytokines such as IL-6, monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor (TNFα), IFN-γ, RANTES, and IL-1β in serum, spleen and other tissues. There were pyknosis and karyorrhexis of lymphocytes in both spleen and cervical lymph nodes and histiocytic and necrotizing lymphadenitis lesions in cervical lymph nodes at the late stage of infection (Matsuno et al, 2017).…”

“…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).…”

Dual Nature of Type I Interferons in SARS-CoV-2-Induced Inflammation

“…To prevent the deleterious effects of chronic inflammation, IFN-I during viral infections is important for causing rapid elimination of the virus, thereby curtailing the immune response [2]. For certain viruses, infection of mice that lack expression of IFN-I receptors can lead to heightened pathology associated with elevated production of proinflammatory cytokines [78]. Specifically, IFN-I acts on T effector cells that eliminate virus and regulatory CD4 + T cells that secrete inhibitory cytokines such as IL-10 [79].…”

Hallmarks of immune response in COVID-19: Exploring dysregulation and exhaustion

“…Additional studies obtained in mice demonstrated a role for type I IFN in the recruitment of proinflammatory cells into the lungs, thus contributing to pathology [ 15 ]. Other mouse models of viral infections have shown that impaired type I IFN response is associated with increased pathology due to the concomitant production of high levels of proinflammatory cytokines [ 16 ]. Supporting this concept, a genetic study has shown that loss of function variants affecting type I IFN response are significantly enriched in patients with life threatening SARS-CoV-2 pneumonia [ 17 ].…”