TLR4 Polymorphisms Mediate Impaired Responses to Respiratory Syncytial Virus and Lipopolysaccharide

Abstract

Severe bronchiolitis following respiratory syncytial virus (RSV) infection occurs in only a small subset of infected infants and the basis for variations in disease severity is not understood. Innate immune responses to RSV are mediated by TLR-4, and the 299Gly and 399Ile alleles of the TLR4 gene have been linked epidemiologically with increased severity of RSV disease in children. We hypothesized that cellular immune responses to RSV mediated by these variant forms of the receptor are defective relative to responses mediated via the common form of the receptor. Human bronchial epithelial cells were transfected with TLR4 constructs encoding the common TLR4 gene sequence (299Asp/399Thr), or the 299Gly or 399Ile alleles, and cytokine responses to in vitro RSV challenge were analyzed in the different transfected cells. Follow-up studies compared RSV-induced responses in PBMC from children expressing these same TLR4 genotypes. Human bronchial epithelial expressing 299Gly or 399Ile displayed normal levels of intracellular TLR4 but failed to efficiently translocate the receptor to the cell surface. This was associated with reduced NF-κB signaling post-TLR4 engagement, reduced production of IFNs, IL-8, IL-10, IL-12p35, IL-18, and CCL8, and the absence of acute-phase TNF-α. These findings were mirrored by blunted PBMC responses to RSV in children expressing the same TLR4 variants. Compromised first-line defense against RSV at the airway-epithelial surface of children expressing these TLR4 variants may thus confer increased susceptibility to severe infections with this virus.

Toll-Like Receptor 4 Polymorphisms in Dengue Virus–Infected Children

“…[5][6][7] Because we could not demonstrate such a difference for dengue, the correlation between the TLR4 polymorphism and RSV infection is likely to be virus specific. Interestingly, our screening of TLR4 polymorphisms showed that the distribution of the TLR4 polymorphism has a high frequency of cosegregated 299/399 in all analyzed groups.…”

“…3 , 4 Children who have the Toll-like receptor 4 (TLR4) polymorphisms Asp299Gly and Thr399Ile were more susceptible to respiratory syncytial virus (RSV), a flavivirus similar to dengue virus. [5][6][7] Therefore, we assessed in children with DHF to see whether these TLR4 polymorphisms influenced susceptibility to and severity of dengue virus infections.…”

Toll-like receptor 4 signaling pathway can be triggered by grass carp reovirus and Aeromonas hydrophila infection in rare minnow Gobiocypris rarus

“…TLR4 polymorphisms mediate impaired responses to respiratory syncytial virus and lipopolysaccharide [34]. Whether GrTLR4b has polymorphisms and whether the polymorphisms relate GCRV disease need further research.…”

“…Further work need be done to use purified LPS from A. hydrophila to more specifically trigger GrTLR4b. In mammals, respiratory syncytial virus (RSV) fusion (F) protein activates cells through TLR4 [6,33,34]. Infection with RSV results in increased expression of TLR4 mRNA and sensitizes airway epithelial cells to endotoxin [35].…”

Çocukluk çağında bronşiyolitler: Etiopatojenez ve immünolojik akciğer hasarındaki yenilikler

“…fiiddetli RSV enfeksiyonu geçirme e¤ilimi olan çocuk-larda SP-A ve SP-D gen polimormizmi iliflkisi gösterilmifltir (36,37). SP-A ve SP-D düzeyi RSV'li hastalarda konrol gurubu hastalara göre daha düflük düzeyde bulunmufltur.…”