Association between Common Toll‐Like Receptor 4 Mutations and Severe Respiratory Syncytial Virus Disease

TLDR

RSV bronchiolitis severity in healthy infants varies widely, suggesting that genetic factors such as TLR4/CD14 innate immune pathways may influence disease outcome. The study genotyped TLR4 Asp299Gly and Thr399Ile mutations and CD14 –159 polymorphism in 99 severe RSV infants and compared them with mild RSV and healthy adult controls. TLR4 Asp299Gly and Thr399Ile mutations were significantly overrepresented in severe RSV cases, whereas the CD14 –159 polymorphism showed no association, indicating that TLR4 variants increase the risk of severe RSV bronchiolitis.

Abstract

The clinical spectrum of respiratory syncytial virus (RSV) bronchiolitis in previously healthy infants is extremely variable. Thus, it is likely that factors such as genetic heterogeneity contribute to disease severity. Toll-like receptor 4 (TLR4) and CD14 are part of a receptor complex involved in the innate immune response to RSV.The association of the TLR4 mutations (Asp299Gly and Thr399Ile) and the CD14/-159 polymorphism were analyzed in 99 infants hospitalized with severe RSV bronchiolitis (group I). Eighty-two ambulatory infants with mild RSV bronchiolitis (group II) and 90 healthy adults (group III) composed the 2 control groups. The TLR4 mutations and the CD14/-159 polymorphism were genotyped by use of reverse-transcriptase polymerase chain reaction and restriction fragment-length polymorphism analysis, respectively.Each of the TLR4 mutations, either alone or in cosegregation, were associated with severe RSV bronchiolitis: the Asp299Gly and Thr399Ile mutations were significantly overrepresented in group I, compared with groups II and III. No association between the CD14/-159 polymorphism and RSV bronchiolitis was found.These findings suggest that TLR4 mutations, but not the CD14/-159 polymorphism, are associated with an increased risk of severe RSV bronchiolitis in previously healthy infants.