Severe fever with thrombocytopenia syndrome (SFTS) is caused by SFTS virus (SFTSV) and is characterized by high mortality and non-specific clinical manifestations, which make early and accurate mol...

To identify metabolic pathways involved in SFTSV pathogenesis, we reanalysed published untargeted metabolomics datasets from 243 patients with SFTSV infection and 132 febrile controls27. This analysis revealed marked metabolic perturbations in serum induced by SFTSV, with 380 differentially abundant metabolites (315 upregulated, 65 downregulated) (Extended Data Fig. 1a,b). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis identified a notable alteration in vitamin A metabolism in SFTSV-infected patients (Fig. 1a). In an independent cohort of 31 patients with SFTSV (24 survivors, 7 deceased) and 15 healthy controls, serum levels of vitamin A were comparable between survivors and control participants but significantly lower in non-survivors (Fig. 1b). Serum IL‑6 levels were significantly lower in survivors than in deceased patients, and a modest inverse correlation between serum IL‑6 and vitamin A levels was observed across the cohort (Fig. 1c). Vitamin A deficiency worsens SFTSV-induced inflammation in a mouse model To validate the link between vitamin A deficiency and systemic inflammatory response syndrome (SIRS), we used a previously established mouse model27,28. In wild-type C57BL/6J mice (referred to as WT B6 hereafter) treated with anti-IFNAR1, SFTSV infection significantly reduced serum vitamin A at 3 and 5 days postinfection (dpi) (Fig. 1d), accompanied by robust...

Lone star virus (LSV) is a bandavirus first isolated from Amblyomma americanum ticks in the United States (U.S.) and is phylogenetically related to severe fever with thrombocytopenia syndrome virus (SFTSV), Heartland virus (HRTV), and Bhanja virus, each of which has been associated with severe human disease. In contrast to these better-characterized bandaviruses, LSV remains poorly studied, and its pathogenic potential is not well defined. Recent detection of LSV RNA in cerebrospinal fluid from an immunocompromised patient in Idaho, U.S., with fatal meningoencephalitis further highlights the need for experimental systems to investigate LSV biology. Here, we rescued recombinant (r) LSV from cloned cDNA and used it to characterize LSV. rLSV replicated similarly to the parental isolate in mammalian cells and caused rapid, systemic, and lethal disease in IFNAR-/- mice, with widespread detection of viral (v) RNA across multiple tissues, hepatic and splenic pathology, and induction of inflammatory cytokines. In contrast, C57BL/6J mice controlled infection and exhibited no clinical disease. To place LSV within a broader comparative framework, we generated rSFTSV from cloned cDNA and compared rLSV, rSFTSV, and HRTV in cell culture and IFNAR-/- mice. Our studies revealed distinct disease kinetics among these related tick-borne bandaviruses and showed that HRTV-induced immunity protected against homologous HRTV rechallenge and heterologous rSFTSV challenge, but not rLSV challenge. Together, these findings establish reverse-genetics platforms and small-animal models for comparative bandavirus studies, define key features of LSV pathogenesis, and place this neglected virus within a framework of related bandaviruses that differ in virulence and immunological overlap.

Lone star virus (LSV) is a bandavirus first isolated from Amblyomma americanum ticks in the United States (U.S.) and is phylogenetically related to severe fever with thrombocytopenia syndrome virus (SFTSV), Heartland virus (HRTV), and Bhanja virus, each of which has been associated with severe human disease. In contrast to these better-characterized bandaviruses, LSV remains poorly studied, and its pathogenic potential is not well defined. Recent detection of LSV RNA in cerebrospinal fluid from an immunocompromised patient in Idaho, U.S., with fatal meningoencephalitis further highlights the need for experimental systems to investigate LSV biology. Here, we rescued recombinant (r) LSV from cloned cDNA and used it to characterize LSV. rLSV replicated similarly to the parental isolate in mammalian cells and caused rapid, systemic, and lethal disease in IFNAR-/- mice, with widespread detection of viral (v) RNA across multiple tissues, hepatic and splenic pathology, and induction of inflammatory cytokines. In contrast, C57BL/6J mice controlled infection and exhibited no clinical disease. To place LSV within a broader comparative framework, we generated rSFTSV from cloned cDNA and compared rLSV, rSFTSV, and HRTV in cell culture and IFNAR-/- mice. Our studies revealed distinct disease kinetics among these related tick-borne bandaviruses and showed that HRTV-induced immunity protected against homologous HRTV rechallenge and heterologous rSFTSV challenge, but not rLSV challenge. Together, these findings establish reverse-genetics platforms and small-animal models for comparative bandavirus studies, define key features of LSV pathogenesis, and place this neglected virus within a framework of related bandaviruses that differ in virulence and immunological overlap.

<p xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="first" dir="auto" id="d1447948e132">Severe fever with thrombocytopenia syndrome (SFTS), caused by the tick-borne severe feve...

Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne phenuivirus causing high mortality in humans. While the nonstru...

Wang et al. report that Gn-specific mAbs from SFTS survivors exhibit broad and potent neutralization, with two providing complete protection in a lethal mouse model. This work maps the Gn antigenic landscape and establishes a deep mutational scanning platform coupled with structural validation for bunyavirus antibody discovery.

by Yan Liu, Meng Xu, Xihua Huang, Xiaohan Liu, Kai Fan, Yingying Zhang, Chen Xing, Hailin Tang, Jiayue Jiang, Kehan Xu, Maozhang He, Gang Xu, Cong Zhang SFTSV, a tick-borne bunyavirus that causes severe fever with thrombocytopenia syndrome (SFTS), exhibits symptoms such as thrombocytopenia, leukocytopenia, hemorrhage, disseminated intravascular coagulation, and even multiple-organ failure. Nevertheless, the underlying pathogenic pathways of this disease remain poorly understood. In this study, by utilizing a lethal mouse model of IFNAR−/− mice, we discovered that complement hyperactivation occurs in the spleen, and the spleen serves as a source of the central complement component C3 in SFTSV-infected mice. Infection of spleen stromal fibroblastic reticular cells with SFTSV significantly induces intracellular complement pathways through a type I IFN-independent manner and generates the active component C3a through the alternative pathway. The transcription of C3 and complement factor B (Cfb) in SFTSV-infected fibroblastic reticular cells is regulated by C/EBP-β. Administration of a C3aR antagonist leads to a reduction in virus load and the inflammatory response, alleviates spleen injury, and prolongs the survival time in IFNAR-/- mice. Collectively, our findings suggest that targeted complement therapy holds potential for the intervention of severe SFTS.

by Yan Liu, Meng Xu, Xihua Huang, Xiaohan Liu, Kai Fan, Yingying Zhang, Chen Xing, Hailin Tang, Jiayue Jiang, Kehan Xu, Maozhang He, Gang Xu, Cong Zhang SFTSV, a tick-borne bunyavirus that causes severe fever with thrombocytopenia syndrome (SFTS), exhibits symptoms such as thrombocytopenia, leukocytopenia, hemorrhage, disseminated intravascular coagulation, and even multiple-organ failure. Nevertheless, the underlying pathogenic pathways of this disease remain poorly understood. In this study, by utilizing a lethal mouse model of IFNAR−/− mice, we discovered that complement hyperactivation occurs in the spleen, and the spleen serves as a source of the central complement component C3 in SFTSV-infected mice. Infection of spleen stromal fibroblastic reticular cells with SFTSV significantly induces intracellular complement pathways through a type I IFN-independent manner and generates the active component C3a through the alternative pathway. The transcription of C3 and complement factor B (Cfb) in SFTSV-infected fibroblastic reticular cells is regulated by C/EBP-β. Administration of a C3aR antagonist leads to a reduction in virus load and the inflammatory response, alleviates spleen injury, and prolongs the survival time in IFNAR-/- mice. Collectively, our findings suggest that targeted complement therapy holds potential for the intervention of severe SFTS.

Read the full paper: Human monoclonal antibodies that target the SFTSV glycoprotein Gn head from four neutralizing epitope groups

a, Schematic illustration of the construction strategy for infectious SFTSV-iRFP reporter virus. This figure was generated using Biorender. b, Replication kinetics of SFTSV-iRFP and SFTSV-wt in Vero cells with a multiplicity of infection (MOI) of 0.5. Virus titers were determined by immunostaining plaque assay (n = 3 independent biological replicates). c, Foci formation of SFTSV-wt and three SFTSV-iRFP passages (P6, P7, and P8) virus in Vero cells as visualized by immunostaining. Experiment was performed in triplicates and repeated two more times with similar results. d, Changes in body weight of A129 mice infected with SFTSV-wt (103 FFUs), SFTSV-iRFP (103 FFUs), or an equal volume of DMEM (Mock group). Initial body weight was set to 100% (n = 6 mice per group). e, Survival curves of A129 mice infected with the indicated viruses (n = 6 per group). f, Representative bioluminescent signal images of SFTSV-iRFP infected mice (103 or 104 FFUs per mouse) at 2 and 4 days post-infection (dpi). The mock and SFTSV-wt-infected mice showed as control (n = 3 mice per group). Data were presented as mean ± standard deviation. The presented images are representative of at least three independent experiments (c and f). Schematic in a created in...

Ren et al. humanize and structurally optimize a chimeric anti-SFTSV antibody, generating variants with markedly enhanced neutralization potency by strengthening binding to recombinant Gn and intact virions, providing full in vivo protection and establishing a generalizable framework for therapeutic antibody engineering.

This study was conducted to investigate tick species that may harbour severe fever with thrombocytopenia syndrome virus (SFTSV) and Babesia microti in the provinces of Henan, Anhui, and Zhejiang, as well as in Shanghai in the central and eastern parts of China. Between March and September 2023, 721 pools of ticks were collected belonging to three genera and five species: Haemaphysalis longicornis (n = 612; 84.9%), Haemaphysalis fusca (n = 94; 13.0%), Rhipicephalus microplus (n = 10; 1.4%), Amblyomma testudinarium (n = 3; 0.4%), and Haemaphysalis wellingtoni (n = 2; 0.3%). The SFTSV-positive pool rate was 20.0%, 13.0%, 5.8%, and 4.1% in Xinyang, Henan; Songjiang, Shanghai; Lu&rsquo;an, Anhui; and Zhoushan, Zhejiang, respectively. SFTSV was detected in all five tick species collected. Among the SFTSV-positive pools, H. longicornis constituted the highest proportion (83.9%, 78/93), whereas pools containing R. microplus and H. wellingtoni each represented the lowest proportion (1.1%, 1/93). Babesia microti was assayed only in these SFTSV-positive tick pools, and co-infection was found in both H. longicornis and H. wellingtoni, though it was most frequent in H. longicornis.

This study was conducted to investigate tick species that may harbour severe fever with thrombocytopenia syndrome virus (SFTSV) and Babesia microti in the provinces of Henan, Anhui, and Zhejiang, as well as in Shanghai in the central and eastern parts of China. Between March and September 2023, 721 pools of ticks were collected belonging to three genera and five species: Haemaphysalis longicornis (n = 612; 84.9%), Haemaphysalis fusca (n = 94; 13.0%), Rhipicephalus microplus (n = 10; 1.4%), Amblyomma testudinarium (n = 3; 0.4%), and Haemaphysalis wellingtoni (n = 2; 0.3%). The SFTSV-positive pool rate was 20.0%, 13.0%, 5.8%, and 4.1% in Xinyang, Henan; Songjiang, Shanghai; Lu&rsquo;an, Anhui; and Zhoushan, Zhejiang, respectively. SFTSV was detected in all five tick species collected. Among the SFTSV-positive pools, H. longicornis constituted the highest proportion (83.9%, 78/93), whereas pools containing R. microplus and H. wellingtoni each represented the lowest proportion (1.1%, 1/93). Babesia microti was assayed only in these SFTSV-positive tick pools, and co-infection was found in both H. longicornis and H. wellingtoni, though it was most frequent in H. longicornis.

The development of versatile vaccine platforms is critical for confronting diverse threats, ranging from infectious diseases to cancer. While existing viral vectors, such as adenovirus (ADV) and vaccinia virus (VACV), represent promising strategies with their distinct advantages, challenges, including pre-existing immunity in human populations and the complexity of their proteomes, highlight the need for novel vector alternatives. Against this backdrop, severe fever with thrombocytopenia syndrome virus (SFTSV)—an emerging pathogenic arbovirus—represents both a serious public health challenge and, as revealed in this issue of Molecular Therapy by Ro et al., a surprising source for a novel solution.

Severe fever with thrombocytopenia syndrome (SFTS) is a viral hemorrhagic fever caused by the SFTS virus (SFTSV), a tick-borne Phlebovirus. This study investigates the association between viral load and cytokine levels in patients with SFTS.MethodsViral RNA was isolated from plasma collected in EDTA and quantified by real-time reverse transcription-polymerase chain reaction (RT-PCR). Cytokines in the sera of SFTS patients were measured using cytometric bead array (CBA).ResultsViral loads ranged from 2.3 × 103 copies/mL to 7.9 × 1011 copies/mL. Of the 46 patients, 10 (21.7%) died during treatment. Viral loads were ≥1 × 108 copies/mL in the patients who died. The concentrations of G-CSF, IFN-α, IFN-γ, IL-1β, IL-6, IL-10, MCP-1, and IP-10 were higher in patients with high viral loads. The levels of IFN-α, IFN-γ, IL-6, MCP-1, and IP-10 positively correlated with SFTSV viral load.ConclusionsSFTSV RNA load was significantly correlated with the concentration of IFN-α, as well as other cytokines (IFN-γ, IL-6, MIP-1α, and IP-10).

ABSTRACTSevere fever with thrombocytopenia syndrome (SFTS) is a disease caused by SFTS virus (SFTSV), an RNA virus, and endemic to Asia. The case fatality rate in Japan is estimated to be approximately 27%. Currently, no efficacious drugs are available. Favipiravir (FPV) has the potential to treat SFTS. However, no quantitative studies comparing FPV with conventional treatments have been conducted in the country. We conducted an open-label, interventional study in which patients with SFTS were administered FPV 1800 mg twice on the first day, followed by 800 mg twice daily for nine days. Additionally, we performed a retrospective observational study on patients with SFTS who received the best supportive care (BSC) without FPV treatment by collecting medical data from individuals at the same institutions. Patients aged 20–85 years were recruited, and blood samples were collected on Days 0 (pre-dose), 1, 3, 6, 9, 14, and 27 in the interventional study. Outcomes and laboratory parameters were compared by 1:1 matching using propensity score (PS). Thirty and 78 patients were enrolled in the FPV and the BSC groups, respectively. Twenty-three pairs were identified by PS matching. The risk ratio of fatality for the FPV group compared to the BSC group reduced to 0.500 after matching. Ferritin levels associated with hemophagocytosis severity were significantly different between the FPV and BSC groups on Days 3 to 9 after matching. No concerning serious adverse events were observed in the FPV group.This interventional study has been registered with the Japan Registry of Clinical Trials as jRCT2080223816.