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Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging bunyavirus that causes severe viral hemorrhagic fever and thrombocytopenia syndrome with a fatality rate of up to 30%. No licensed vaccines or therapeutics are currently available for humans. Here, we develop seven monoclonal antibodies (mAbs) against SFTSV surface glycoprotein Gn. Mechanistic studies show that three neutralizing mAbs (S2A5, S1G3, and S1H7) block multiple steps during SFTSV infection, including viral attachment and membrane fusion, whereas another neutralizing mAb (B1G11) primarily inhibits the viral attachment step. Epitope binning and X-ray crystallographic analyses reveal four distinct antigenic sites on Gn, three of which have not previously been reported, corresponding to domain I, domain II, and spanning domain I and domain II. One of the most potent neutralizing mAbs, S2A5, binds to a conserved epitope on Gn domain I and broadly neutralizes infection of six SFTSV strains corresponding to genotypes A to F. A single dose treatment of S2A5 affords both pre- and post-exposure protection of mice against lethal SFTSV challenge without apparent weight loss. Our results support the importance of glycoprotein Gn for eliciting a robust humoral response and pave a path for developing prophylactic and therapeutic antibodies against SFTSV infection. Ren et al. generate a panel of monoclonal antibodies (mAbs) that recognize distinct epitopes on the glycoprotein Gn and neutralize severe fever with thrombocytopenia syndrome virus (SFTSV) by diverse mechanisms. One most potent mAb targeting the Gn domain I provides protection against lethal SFTSV infection in mice.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging viral infectious disease caused by a novel Bandavirus in the family Phenuiviridae . The SFTS virus (SFTSV) is transmitted to various hosts, including humans, through tick bites, leading to high fever, thrombocytopenia, and leukopenia, with a high case fatality rate (up to 30%) due to multiple organ dysfunction. Therefore, early diagnosis is crucial for effective treatment and preventing disease transmission. In this study, we aimed to develop and characterize monoclonal antibodies targeting the SFTSV nucleocapsid protein (NP). We generated recombinant NP to screen antibodies against SFTSV. Using phage display technology, we identified candidate single-chain variable fragment (scFv) sequences capable of detecting SFTSV NP. Five human IgG antibodies and six chimeric mouse antibodies exhibited strong binding ability to the recombinant NP. Furthermore, their specificity and selectivity were evaluated against NPs from different subtypes and other viral species. A sandwich enzyme–linked immunosorbent assay (ELISA) was performed to determine optimal antibody pairings for SFTSV detection. The mP01A05/hP01C09, mP01A05/hP01B10, and mP02E04/hP01A05 antibody pairs demonstrated high efficacy in diagnosing SFTSV infections. These findings provide valuable antibody resources and establish an effective platform for the diagnosis of SFTS. Key points • Monoclonal antibodies targeting SFTSV NP were developed using phage display technology. • Candidate antibodies showed strong binding ability and high specificity to SFTSV NP. • Optimized antibody pairs enabled effective SFTSV detection via sandwich ELISA.

Severe fever with thrombocytopenia syndrome (SFTS) is a new tick-borne viral disease, and most SFTS virus (SFTSV) infections occur via bites from the tick Haemaphysalis longicornis ; however, SFTSV transmission can also occur through close contact with an infected patient. SFTS is characterized by acute high fever, thrombocytopenia, leukopenia, elevated serum hepatic enzyme levels, gastrointestinal symptoms, and multiorgan failure and has a 16.2 to 30% mortality rate. In this study, we found that age, dyspnea rates, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase, multiorgan dysfunction score (MODS), viral load, IL-6 levels, and IL-10 levels were higher in patients with fatal disease than in patients with nonfatal disease during the initial clinical course of SFTS. In addition, we found that IL-6 and IL-10 levels, rather than viral load and neutralizing antibody titers, in patients with an SFTSV infection strongly correlated with outcomes (for severe disease with an ultimate outcome of recovery or death).

Severe fever with thrombocytopenia syndrome virus (SFTSV), a tick-borne bunyavirus, causes an emerging viral hemorrhagic fever with a high mortality rate. SFTSV nonstructural protein S (NSs) is a virulence factor that sequesters antiviral proteins into autophagic vesicles for degradation to escape host immune response. SAFA (Nuclear scaffold attachment factor A), an RNA sensor, recognizes viral RNA and is retained in the cytoplasm upon RNA virus SFTSV infection and then activates innate immunity. It is unclear whether NSs mediates the escape of SAFA-mediated antiviral response. Here we showed that SFTSV NSs can inhibit SAFA-dependent antiviral response via autophagy. We used SAFA-NLS (the nuclear localization signal) mutant to transfect SAFA knocked-out MEF cells and found that the cytoplasmic SAFA promoted innate immune response to poly(I:C) stimulating. Importantly, NSs interacted with the AAA+ domain of SAFA and retained SAFA in the cytoplasm thereby suppressing SAFA-mediated antiviral response. Mechanistically, SFTSV NSs degraded cytoplasmic SAFA via SQSTM1/p62-dependent autophagy and sequestered SAFA into autophagic vesicles for degradation through promoting the interaction between SAFA and LC3. In conclusion, our results indicate a novel mechanism of SFTSV NSs to escape host antiviral immune response by recruiting SAFA into autophagic flux for degradation.

Aging significantly influences host immune responses to viral infections, including Severe Fever with Thrombocytopenia Syndrome Virus (SFTSV), which is associated with high mortality in elderly patients. Despite its high fatality rate and pandemic potential, effective therapies remain unavailable, and the age-dependent mechanisms underlying SFTSV pathogenesis are not fully understood. To address this gap, we employed a ferret model (an immunocompetent animal model that mimics human SFTSV infections) and performed multi-tissue single-cell RNA sequencing and histopathological analyses. Our results reveal that, upon SFTSV infection, aged ferrets experience extensive decrease of critical immune cells (particularly B and T cells) due to infection-induced cell death and excessive hemophagocytosis in hematopoietic organs, whereas young-adult ferrets rapidly clear the virus with minimal lymphocyte changes. Notably, aged ferrets display marked immune dysregulation, characterized by non-specific activation of T-bet  ⁺ age-associated memory B cells ( T-bet + ABCs) and the proliferation of defective plasmablasts ( MKI67  ⁺ PB1), which serve as major viral reservoirs and drive systemic viral dissemination. Comparative analysis further demonstrated that the MKI67  ⁺ PB1 subset dominates SFTSV⁺ cells in both aged ferrets and human fatal cases, exhibiting the highest per-cell viral UMI counts. Moreover, monocytes and macrophages in aged ferrets exhibit heightened inflammatory gene expression, contributing to the hyper-inflammatory state observed during infection. Collectively, these insights underscore the critical role of dysregulated memory B cell responses and hyper-inflammation in age-dependent SFTSV pathogenesis, highlighting potential targets for interventions in elderly populations.

The genus Bandavirus consists of seven tick-borne bunyaviruses, among which four are known to infect humans. Dabie bandavirus , severe fever with thrombocytopenia syndrome virus (SFTSV), poses serious threats to public health worldwide. SFTSV is a tick-borne virus mainly reported in China, South Korea, and Japan with a mortality rate of up to 30%. To date, most immunology-related studies focused on the antagonistic role of SFTSV non-structural protein (NSs) in sequestering RIG-I-like-receptors (RLRs)-mediated type I interferon (IFN) induction and type I IFN mediated signaling pathway. It is still elusive whether the interaction of SFTSV and other conserved innate immune responses exists. As of now, no specific vaccines or therapeutics are approved for SFTSV prevention or treatments respectively, in part due to a lack of comprehensive understanding of the molecular interactions occurring between SFTSV and hosts. Hence, it is necessary to fully understand the host-virus interactions including antiviral responses and viral evasion mechanisms. In this review, we highlight the recent progress in understanding the pathogenesis of SFTS and speculate underlying novel mechanisms in response to SFTSV infection.

Severe Fever with Thrombocytopenia Syndrome Virus (SFTSV), a tick-borne phlebovirus first identified in China, causes severe illness characterized by high fever, thrombocytopenia, leukopenia, and, in some cases, multi-organ failure and death. With mortality rates ranging from 5% to 30% in endemic regions, SFTSV has emerged as a significant public health threat across East Asia, including South Korea and Japan, with potential for broader outbreaks. This review synthesizes recent advances in SFTSV animal models and candidate vaccines, highlighting their contributions and limitations. Current animal models, including mice, ferrets, and non-human primates, partially replicate human disease but fail to fully recapitulate clinical manifestations, limiting their translational utility. Vaccine development has shown promise, with candidates such as mRNA, subunit, and viral vector vaccines demonstrating efficacy in preclinical studies, yet none have progressed to clinical trials. Key challenges include viral genetic diversity and immune evasion. Future research should focus on refining animal models to better mimic human pathology, developing broad-spectrum vaccines, and integrating virological and immunological insights to enhance prevention and treatment strategies for SFTSV.

Severe fever with thrombocytopaenia syndrome virus (SFTSV), an emerging tick-borne pathogen, causes haemorrhagic fever in infected patients and is associated with a high mortality rate in humans. The imperative need for vaccines against this lethal virus is underscored by a lack of effective preventive measures. The results of this study yield notable advancements: the successful development of an SFTSV mRNA vaccine encoding the glycoprotein C (Gc) gene, achieving N-linked glycosylation in the expressed protein. This vaccination regimen induced a balanced TH1/TH2 immune response and elicited robust levels of both cellular and humoral immunity in C57BL/6 and IFNAR−/− mice. The results of the present study demonstrate that immunization with 1 μg mRNA vaccine provides complete protection (100 %) against lethal SFTSV infection (77,000 LD50) in IFNAR−/− mice. Moreover, the vaccine candidate induces long-lasting immunity and confers protection against SFTSV for at least six months. Notably, the antibody provides 100 % protection according to passive transfer assays, suggesting that humoral immunity plays a crucial role in resisting SFTSV challenge. These findings present a promising stride forward in the quest for an effective vaccine against SFTSV, highlighting the potential of the developed mRNA vaccine in conferring substantial immunity. •Developed an SFTSV mRNA vaccine with N-glycosylation modifications to Gc gene.•Achieved 100 % protection against lethal SFTSV infection in mice with 1 μg dose.•Induced long-lasting immunity effective for at least six months post-vaccination.•Antibodies confer complete protection, underscoring humoral immunity's critical role.

Severe fever with thrombocytopenia syndrome (SFTS) is a viral hemorrhagic fever caused by a tick-borne virus SFTSV with a mortality rate of up to 30%. Currently, there is no vaccine or effective therapy for SFTS. Neutralizing monoclonal antibody therapy, which provides immediate passive immunity and may limit disease progression, has emerged as a reliable approach for developing therapeutic drugs for SFTS. In this study, 4 human monoclonal antibodies (hmAbs) derived from convalescent SFTS patients’ lymphocytes based on human single-chain variable fragment antibody libraries were tested for their neutralizing activities in cells and their treatment effect in animals individually and in pair combinations. The neutralization test showed that all 4 hmAbs exhibited strong neutralizing activity against SFTSV infection in vitro . The protection rate of hmAbs 4-6, 1F6, 1B2, and 4-5 against SFTSV lethal challenge in IFNAR1 -/- A129 mice are 50%, 16.7%, 83.3%, and 66.7%, respectively. Notably, the pair combination of antibodies (1B2 and 4-5, 1B2 and 1F6) that recognized distinct epitopes protected 100% of mice against SFTSV lethal challenge. In conclusion, our findings indicate that the pair combinations of hmAbs 1B2 and 4-5 or hmAbs 1B2 and 1F6 may serve as promising therapeutic drugs for treating SFTSV infection.

Severe fever with thrombocytopenia syndrome virus (SFTSV) is a representative high-pathogenic bandavirus ( Bandavirus genus, Phenuiviridae family). Inducible expression of interferon-stimulated genes (ISGs) is the foundation of host antiviral defense; however, their roles in bandavirus infection remain elusive. Here, we identify over 200 ISGs potentially inhibiting or promoting bandaviral replication. With SFTSV as the main model, we further systematically uncover the notable antiviral role of one ISG, cyclin D3 (CCND3), against bandaviruses. SFTSV infection induces CCND3 up-regulation and cytoplasmic translocation. CCND3, in turn, inhibits the viral replication in cultured cells and pathogenicity in vivo. The viral nucleoprotein (NP) is the target of CCND3. By its CN domain, CCND3 interacts with NP’s “head” region in an RNA-independent manner, suppressing the ribonucleoprotein (RNP) replication machinery activity. Furthermore, consistent with interaction interface mapping and structural modeling analyses, the CCND3-NP interaction blocks NP multimerization, NP-RNA binding, and NP association with viral polymerase, that is, the NP activities essential to RNP construction and functioning. Conversely, the viral nonstructural protein, NSs, can partially antagonize CCND3 by attenuating its induction and promoting autophagic degradation. These findings provide new insights into bandavirus-host interactions and arms race, advancing the understanding of bandavirus infection and probably informing antiviral therapeutic development. Here, the authors identify >200 host proteins regulating bandavirus replication via an ISG library screen. With SFTSV as the main model, they then uncover a notable antiviral mechanism of CCND3 and the viral antagonism, offering new insights into virus-host interplays.