First Report of IFITM3 Polymorphism Associated with Severe Fever with Thrombocytopenia Syndrome Virus (SFTSV) Infection in the Raccoon Dog

Severe fever with thrombocytopenia syndrome virus (SFTSV), a novel Phlebovirus within the family Phenuiviridae, is the causative agent of severe fever with thrombocytopenia syndrome (SFTS), a tick-borne zoonotic disease. Raccoon dogs (Nyctereutes procyonoides) have been identified as potential reservoirs of SFTSV. Interferon-induced transmembrane protein 3 (IFITM3) plays a critical role in the host antiviral response and has been implicated in restricting SFTSV infection. This study investigated the association between IFITM3 gene polymorphisms and susceptibility to SFTSV infection in raccoon dogs. Genotype, allele, and haplotype frequencies were compared between healthy and SFTSV-infected animals. In addition, in silico programs were used to evaluate the functional impact of a 3′ untranslated region (UTR) single-nucleotide polymorphism (SNP) (c.447+34G>A) and a non-synonymous SNP (c.52C>T, P18S). Furthermore, the 3D structure modeling was performed to assess structural alterations associated with the P18S variant. A significant difference in genotype frequency of the c.447+34G>A SNP was observed between healthy and SFTSV-infected raccoon dogs. RNAfold and CentroidFold predict that this SNP (c.447+34G>A) affects RNA structure and energy. Functional predictions from PolyPhen-2 and SIFT indicated that the c.52C>T (P18S) substitution may be deleterious, although E-SNPs & GO classified it as benign. Structural modeling suggested that the P18S variant alters local hydrogen bonding, potentially affecting protein stability and flexibility. This study presents the first genetic association analysis of IFITM3 polymorphisms in raccoon dogs. Our findings suggest a potential link to SFTSV susceptibility, emphasizing the potential role of host genetic variation in modulating SFTSV susceptibility.