Exploration of immunological responses underpinning severe fever with thrombocytopenia syndrome virus infection reveals IL-6 as a therapeutic target in an immunocompromised mouse model

Abstract

Dabie bandavirus (previously severe fever with thrombocytopenia syndrome virus; SFTSV) is an emerging tick-borne bunyavirus responsible for severe fever with thrombocytopenia syndrome (SFTS), a disease with high case fatality that is characterised by high fever, thrombocytopenia, and potentially lethal haemorrhagic manifestations. Currently, neither effective therapeutic strategies nor approved vaccines exist for SFTS. Therefore, there remains a pressing need to better understand the pathogenesis of the disease and to identify therapeutic strategies to ameliorate SFTS outcomes. Using a type I interferon (IFN)-deficient mouse model, we investigated the viral tropism, disease kinetics and the role of the virulence factor non-structural protein (NSs) in SFTS. Ly6C+ MHCII+ cells in the lymphatic tissues were identified as an important target cell for SFTSV. Advanced SFTS was characterised by significant migration of inflammatory leukocytes, notably neutrophils, into the lymph node and spleen, however, these cells were not required to orchestrate the disease phenotype. The development of SFTS was associated with significant upregulation of pro-inflammatory cytokines, including high levels of IFN-γ and IL-6 in the serum, lymph node and spleen. Humoral immunity generated by inoculation with delNSs SFTSV was 100% protective. Importantly, NSs was critical to the inhibition of the host IFNɣ response or downstream interferon stimulated gene production and allowed for the establishment of severe disease. Finally, therapeutic but not prophylactic use of anti-IL-6 antibodies significantly increased the survival of mice following SFTSV infection and therefore this treatment modality presents a novel therapeutic strategy for treating severe SFTS.

Tocilizumab therapy for IL-6 increment in a patient with non-fatal severe fever with thrombocytopenia syndrome

“…Furthermore, in 2022, it was recommended for the management of patients with severe COVID-19 in South Korea ( Korean Society of Infectious Diseases 2022 ). In a recent SFTS animal study, the administration of an anti-IL-6 antibody, when disease progressed from mild to moderate, significantly increased the survival of the infected animals ( Bryden et al, 2022 ). The above-mentioned studies support a therapeutic strategy of inhibiting IL-6 pathways in patients with SFTS.…”

“…The development of SFTS has been associated with the significant upregulation of proinflammatory cytokines, including high levels of interferon (IFN)γ and interleukin (IL)-6 ( Yoo et al, 2021 ). Nonetheless, anti-IL-6 antibodies significantly increased the survival of mice with SFTS ( Bryden et al, 2022 ). Herein, we report for the first time, the early application of an anti-IL-6 antibody in a patient with SFTS.…”

Construction and Characterization of Severe Fever with Thrombocytopenia Syndrome Virus with a Fluorescent Reporter for Antiviral Drug Screening

“…The entrapped molecules are mainly involved in host type I IFN induction and signaling pathways, such as those involving the protein kinase TBK1, RIG-I, interferon regulatory factor (IRF)-3, IRF-7, STAT1, and STAT2 [ 13 , 14 , 15 , 16 , 17 ]. Furthermore, in vivo studies indicated that recombinant SFTSV that lacked NSs had limited pathogenicity in aged ferrets and type I IFN receptor-deficient (IFNAR −/− ) mice [ 18 , 19 ]. Therefore, NSs are the virulence factors of SFTSV.…”

Coinfections in hospitalized patients with severe fever with thrombocytopenia syndrome: A retrospective study

“…4 Several lines of evidence had supported cellular immunosuppression and immune paralysis that ensued by SFTSV infection, which led to overproduction of pro-and anti-inflammatory mediators. 5 Systemic inflammatory response syndrome and compensatory anti-inflammatory response syndrome resulting from SFTSV infection also increase susceptibility to coinfections. 6,7 Coinfection in severe cases of SFTS had been reported, with invasive pulmonary aspergillosis (IPA) as the most frequent pathogenic infection.…”

“…In severe SFTS patients, coinfection readily occurs as a result of the dysregulated immune system of the host 4 . Several lines of evidence had supported cellular immunosuppression and immune paralysis that ensued by SFTSV infection, which led to overproduction of pro‐ and anti‐inflammatory mediators 5 . Systemic inflammatory response syndrome and compensatory anti‐inflammatory response syndrome resulting from SFTSV infection also increase susceptibility to coinfections 6,7 …”