Age-dependent pathogenicity of two severe fever with thrombocytopenia syndrome viruses in a ferret model

SFTSV is an emerging tick-borne pathogen associated with high case fatality rates, particularly in elderly patients. While severe pathogenicity has been reported in aged ferrets, lethal or clinically significant infection in younger animals and genotype-dependent differences in pathogenicity remain insufficiently defined. In this study, we established a ferret infection model using two Korean clinical isolates representing genotypes B and F and systematically compared disease progression between one-year-old and three-year-old ferrets. Three-year-old ferrets exhibited rapid fever onset, marked body weight loss, early clinical deterioration, severe thrombocytopenia and leukopenia, significant elevations in AST and ALT levels, and earlier peak viremia with higher tissue viral loads, indicating impaired early viral control and accelerated systemic dissemination. Notably, one-year-old ferrets also developed measurable pathogenic manifestations, including febrile responses, progressive weight loss, detectable viremia, and multiorgan viral distribution, although disease progression was delayed and less severe compared with older animals. Within the same age group, differences in pathogenicity between genotypes B and F were limited. These findings demonstrate that host age is a major determinant of SFTSV disease severity and support the use of an age-stratified ferret model for preclinical evaluation of vaccines and antiviral therapeutics. ImportanceSFTS is an emerging tick-borne disease that can cause high fever, thrombocytopenia, and multi-organ failure, with particularly severe outcomes in older adults. Currently, no approved vaccines or specific antiviral treatments are available. Reliable animal models that recapitulate human disease are therefore essential for the development of effective countermeasures. Ferrets have recently been proposed as a useful model for SFTS, especially in aged animals, but the susceptibility of younger ferrets and the impact of viral strain differences remain unclear. Here we show that host age strongly determines disease severity in ferrets infected with two genetically distinct SFTS virus strains, establishing a flexible animal model for evaluating vaccines and antiviral therapies.