From Lab Dishes to Ferrets: Mapping the Preclinical Models of SFTS Virus

Bandavirus dabieense, the tick-borne virus behind severe fever with thrombocytopenia syndrome (SFTS), has long outpaced the tools available to study it. First identified in China in 2009 and formally reclassified by the International Committee on Taxonomy of Viruses in 2019, the virus now causes disease across East and Southeast Asia, including South Korea, Japan, Vietnam, and Thailand, with case fatality rates that vary across outbreaks and study cohorts. Yet the mechanisms driving its pathogenesis remain poorly defined, and no specific antiviral therapy has been approved. A new review published in Frontiers in Cellular and Infection Microbiology takes stock of the experimental systems researchers have assembled to close that gap, from interferon-deficient mice to aged ferrets and companion animals, and argues that the field’s central limitation is no longer a lack of models but a mismatch between what each model can do and what scientists ask of it.

The review, authored by researchers at Beijing Ditan Hospital of Capital Medical University, is framed as a critical narrative review rather than a formal systematic analysis. During revision, the authors conducted a retrospective structured search of PubMed/MEDLINE and the Web of Science Core Collection on October 14, 2026, retrieving 464 records from each database. After deduplication removed 429 overlapping records, 499 unique entries remained, and manual cross-checking of reference lists added eight further model-focused references. The final synthesis rests on 59 citations. The authors are explicit that these counts document transparency rather than a prospectively designed systematic review, and they appraised each model qualitatively against seven domains: clinical and phenotypic validity, virological fidelity, immunological validity, reproducibility, feasibility, throughput, and purpose-specific utility.

Understanding why models matter requires understanding the virus itself. DBV is an enveloped, negative-sense RNA virus with virions roughly 80 to 100 nanometers in diameter and a tripartite genome. Its large segment encodes the RNA-dependent RNA polymerase that drives transcription and replication; its medium segment yields the Gn and Gc envelope glycoproteins that mediate cell entry and serve as the primary targets of neutralizing antibodies; and its small segment produces the nucleoprotein plus the nonstructural protein NSs, a major virulence determinant that antagonizes host innate immune signaling. In humans, infection produces fever, thrombocytopenia, leukopenia, gastrointestinal symptoms, and multi-organ dysfunction, with severe cases progressing to neurological complications, shock, and death. Fatal cases show viral antigen in macrophages and B-lineage cells within secondary lymphoid tissues, along with lymphoid depletion and tissue necrosis in the spleen and lymph nodes.

The clinical picture is one of immune dysregulation as much as viral replication. Severe infection is frequently accompanied by elevated inflammatory mediators including IL-6, IL-1β, and other cytokines linked to systemic inflammation, while fatal cases may show defective virus-specific antibody responses and disturbed B-cell and T-cell function that sustain viremia. Advanced age is consistently associated with severe disease and mortality, as are diabetes, hypertension, high viral loads, and coagulation abnormalities. These clinical associations, the review stresses, should be distinguished from factors that merely raise exposure risk, such as agricultural work and tick contact. They also shape model choice: interferon-deficient systems suit replication and antiviral studies, whereas models retaining functional immunity are better positioned to examine age-associated susceptibility and inflammatory injury.

In vitro systems remain the workhorses of DBV research. Vero and Vero E6 cells, derived from African green monkey kidney and deficient in type I interferon production, support efficient viral replication and underpin isolation, propagation, and high-throughput drug screening; screening of FDA-approved compound libraries in these cells identified ribavirin and favipiravir as inhibitors of DBV replication, and additional entry inhibitors and natural products such as bergamottin and hexachlorophene have been evaluated on the same platform. Human hepatocyte-derived lines like HepG2 and Huh-7, which are permissive to infection, allow studies of liver injury and of compounds requiring hepatic metabolic activation, including calcium channel blockers such as benidipine. Primary cells add physiological relevance: DBV infection disrupts intercellular junctions in human umbilical vein endothelial cells, increasing permeability, while primary macrophages support viral replication and undergo NLRP3 inflammasome-driven pyroptosis, a process that platelets appear to attenuate.

The animal model landscape is defined by a stubborn obstacle: most immunocompetent small animals resist clinical infection. Across 12 wild-type mouse strains challenged with a high dose of the SD4 strain, researchers observed neither fatal outcomes nor overt histopathological lesions, and even aged C57BL/6 mice showed only transient weight loss. To bypass this restriction, researchers disable type I interferon signaling. IFNAR-neutralizing antibodies induce susceptibility with hepatic necrosis and splenic white pulp atrophy, but genetically ablated IFNAR-deficient C57BL/6 mice provide a uniformly lethal model marked by extreme viremia, severe thrombocytopenia, and a cytokine storm involving IL-12, IL-6, IL-1α, IL-1β, and IFN-γ. This model also captures neuroinvasion, in which microglial activation drives neurotoxic A1 reactive astrocytes and neuronal death, and it has become the primary platform for testing favipiravir, ribavirin, neutralizing antibodies, and vaccine candidates.

Other mouse variants fill specific niches. Neonatal wild-type mice, whose immunity is immature, develop severe central nervous system infection without genetic ablation; in neonatal C57BL/6 mice, intraperitoneal infection reportedly penetrates the blood-brain barrier within three hours, producing high brain viral loads and massive neuronal damage. Humanized mice, created by engrafting human peripheral blood mononuclear cells into immunodeficient NCG mice, develop thrombocytopenia, leukopenia, cytokine storms, and multi-organ injury, making them uniquely suited to human-specific biologics despite donor-dependent variability. A separate approach delivers the human entry receptor DC-SIGN into wild-type mice via an AAV2 vector, granting permissiveness without ablating native immunity. In hamsters, STAT2-knockout animals lacking type I and III interferon signaling develop severe disease with profound thrombocytopenia and hepatic and splenic viral dissemination; favipiravir given prophylactically or early conferred complete protection in this model, while ribavirin failed to provide meaningful survival benefit.

Among larger animals, ferrets stand out because they recapitulate age-dependent severity with an intact immune system. Young adult ferrets mount effective antiviral responses and show only mild, transient illness, whereas aged ferrets develop profound thrombocytopenia, leukopenia, sustained fever, multi-organ viral dissemination, and mortality of up to 93 percent under experimental challenge, a figure the authors caution may not reflect overall human case fatality. The aged ferret platform validated a self-assembling Gn head-ferritin nanoparticle vaccine that completely prevented clinical manifestations. Route of inoculation matters sharply: intramuscular and subcutaneous challenge in aged ferrets produced 100 percent mortality, while intravascular inoculation yielded 25 percent mortality despite comparable early signs. Cats, by contrast, are highly susceptible and develop lethal hyperinflammatory disease with necrotizing lymphadenitis and hemophagocytosis, making them valuable for immunomodulatory testing, though outbred populations introduce variability and high viral shedding raises biosafety concerns. Dogs are relatively resistant, showing mild or asymptomatic infection unless pharmacologically immunosuppressed, and an inactivated DBV vaccine cleared viremia in challenged dogs.

Non-human primates, despite their physiological similarity to humans, have proved frustratingly resistant. Rhesus macaques mount virus-specific IgM, IgG, and neutralizing antibodies but develop only mild, self-limiting disease, with low-grade fever and transient cytopenias; notably, viral RNA can persist in lymphoid tissues and bone marrow after viremia becomes undetectable, suggesting clinical recovery does not guarantee complete viral clearance. Cynomolgus macaques show an even higher threshold, displaying negligible signs even after high-dose challenge. The review identifies developing a permissive NHP model, potentially through targeted interferon pathway disruption, as a critical priority for validating host-directed therapies before clinical trials.

The authors’ conclusion is a call for model strategy rather than model collection. No single system reproduces the combined features of severe human SFTS, and each captures only discrete components: reductionist cell cultures define mechanisms, interferon-deficient rodents establish in vivo antiviral activity, immunocompetent ferrets and cats reflect inflammatory complexity, and resistant hosts illuminate viral control. Advanced platforms may narrow the gap; recent work in human pancreatic organoids showed that DBV replicates within structured tissues through entry factors including CCR2 and LRP1, inducing cell death and inflammatory amplification invisible in monolayer cultures. Until such systems mature, the review contends, progress will depend on matching each experimental question to the model whose strengths fit it, and validating key findings across complementary platforms.

Subject of Research: Preclinical cellular and animal models of Bandavirus dabieense (SFTS virus) infection

Article Title: Preclinical models of Bandavirus dabieense infection: insights into pathogenesis, host responses, and translational applications

Article References: Peng, W., Zhang, R., Wang, J., Jiang, Z., & Chen, Z. (2026). Preclinical models of Bandavirus dabieense infection: insights into pathogenesis, host responses, and translational applications. Frontiers in Cellular and Infection Microbiology, 16, Article 2007854. https://doi.org/10.3389/fcimb.2026.2007854

Image Credits: AI Generated

DOI: 10.3389/fcimb.2026.2007854

Keywords: Bandavirus dabieense, SFTS, preclinical models, IFNAR-deficient mice, ferrets, antiviral testing, vaccine development, tick-borne virus, humanized mice, non-human primates, Preclinical, models