Association of TLR4 polymorphisms with symptomatic respiratory syncytial virus infection in high-risk infants and young children

Respiratory syncytial virus (RSV) is a leading cause of infant mortality worldwide. Although anfi-RSV Ab prophylaxis has greatly reduced infant mortality in the United States, there is currently no vaccine or effective antiviral therapy. RSV fusion (F) protein activates cells through TLR4. Two single nucleotide polymorphisms (SNPs) encoding Asp299Gly and Thr3991le substitutions in the TLR4 ectodomain were previously associated with TLR4 hyporesponsiveness and increased susceptibility to bacterial infection. Prevalence of these SNPs was analyzed in a case series of 105 DNA samples extracted from archived nasal lavage samples from high-risk infants/young children with confirmed RSV disease who participated in two seminal clinical trials for anti-RSV prophylaxis. Frequencies of TLR4 SNPs in the case series were compared with those of literature controls, healthy adults, infants, and young children who presented with symptoms of respiratory infections (but not preselected for high risk for RSV). Both SNPs were highly associated with symptomatic RSV disease in this largely premature population (p < 0.0001), with 89.5% and 87.6% of cases being heterozygous for Asp299GIy and Thr3991le polymorphisms versus published control frequencies of 10.5% and 6.5%, respectively. The other two control groups had similarly low frequencies. Our data suggest that heterozygosity of these two extracellular TLR4 polymorphisms is highly associated with symptomatic RSV disease in high-risk infants and support a dual role for TLR4 SNPs in prematurity and increased susceptibility to RSV not revealed by analysis of either alone.