Host genetic factors modulating dengue virus: a systematic review of TLR polymorphisms

Dengue virus (DENV) infection is a substantial global public health burden, affecting ~ 390 million people every year, with a mortality rate of ~ 2.5% of those requiring hospitalization. Despite implementing vaccination and outbreak controls, DENV infection incidence continues to rise, particularly in endemic tropical and subtropical regions. Toll-like receptors (TLRs), as key components of the innate immune system, play a crucial role in recognizing DENV and initiating immune responses. Genetic variations, such as single-nucleotide polymorphisms (SNPs), in TLR genes may alter their function and expression levels, which in turn affect an individual's susceptibility to dengue and the severity of the disease. Defining these associations is critical for dengue risk stratification, prognosis, treatment strategies, and vaccine development. Currently, no review has comprehensively defined these associations; therefore, this study aimed to systematically evaluate TLR gene variants and their association with DENV infection susceptibility and severity.

A systematic search was performed across major databases, including PubMed/MEDLINE, EMBASE, Scopus, and Web of Science, covering reports published up to April 20, 2025. Prospective or retrospective observational studies (case-control and cohort) investigating the association between TLR SNPs and dengue susceptibility and severity were included. Descriptive data were independently extracted by two reviewers using a standardized workflow, and bias risk was assessed using an adapted Newcastle-Ottawa Scale for case-control studies.

Eight case-control studies from India, Mexico, Colombia, and Indonesia met the inclusion criteria from an initial 65 records. All the included studies were assessed as having acceptable quality. Although studies demonstrate heterogeneity in their methods, TLR3 rs3775291 and rs3775290, TLR4 rs4986790 and rs4986791, and TLR7 rs179008 and rs3853839 were among the most studied SNPs that exhibited correlation with dengue susceptibility and/or severity.

Certain SNPs in TLR3, TLR4, TLR7, TLR8, and TLR9 demonstrate associations with dengue susceptibility. All of these, except TLR4 and TLR9, demonstrated some correlation with severity and/or certain clinical outcomes. The heterogeneity and limitations of the reviewed studies, as indicated by finding discrepancies, highlight the complexity of these genetic associations. Therefore, further large-scale, multi-ethnic prospective studies with standardized methodologies and functional validation are required to clarify the role of TLR SNPs in dengue pathogenesis.

Not applicable.