The Role of TLR3 rs3775291 Variant in West Nile Virus Infection: A Case-Control Study

West Nile virus (WNV) causes human disease with variable severity. Toll-like receptor 3 (TLR3) is essential for innate immune responses to viral infections, including WNV. The non-synonymous single-nucleotide polymorphism (SNP) rs3775291 (C/T), which alters TLR3 function, has been linked to susceptibility to several viral pathogens, but its role in WNV infection is unclear. This study investigates the association between rs3775291 and WNV infection in hospitalized patients. A case-control study was conducted in Cyprus, including 20 hospitalized WNV patients and 22 healthy controls (HCs). Genotyping was performed using a TaqMan allelic discrimination assay. The C/T genotype was significantly more frequent in WNV patients (65%) than in HCs (27.3%) (p = 0.0217; OR = 0.1648, 95% CI: 0.04073-0.6731). C/T and T/T genotypes combined were more common in patients (75%) versus HCs (36.4%) (p = 0.0157; OR = 0.1905, 95% CI: 0.05017-0.7232). The T allele was more frequent in patients, but not statistically significant (p = 0.0640). The results indicate that the C/T genotype is associated with increased susceptibility to WNV infection and the likelihood of hospitalization. Further studies in larger, independent cohorts and across diverse populations and age groups are warranted to validate these findings.