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An In vitro Model to Study Immune Responses of Human Peripheral Blood Mononuclear Cells to Human Respiratory Syncytial Virus Infection
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TLR4 polymorphisms mediate impaired responses to respiratory syncytial virus and lipopolysaccharide

Meri K Tulic1, Robert J Hurrelbrink, Cecilia M Prêle

  • 1Division of Cell Biology, Telethon Institute for Child Health Research, Centre for Child Health Research, University of Western Australia, West Perth, WA 6872, Australia.

Journal of Immunology (Baltimore, Md. : 1950)
|June 21, 2007
PubMed

Insights

Toll-like receptor 4 (TLR4) gene variants (299)Gly or (399)Ile impair cellular immune responses to respiratory syncytial virus (RSV). This compromised defense increases susceptibility to severe RSV infections in children.

Area of Science:

  • Immunology
  • Genetics
  • Pediatrics

Background:

  • Severe bronchiolitis in infants is often caused by respiratory syncytial virus (RSV), but the reasons for varying disease severity are unknown.
  • Innate immune responses to RSV involve Toll-like receptor 4 (TLR4). Specific TLR4 gene alleles, (299)Gly and (399)Ile, are epidemiologically linked to more severe RSV disease in children.

Purpose of the Study:

  • To investigate whether cellular immune responses mediated by common versus variant TLR4 forms differ in their effectiveness against RSV.
  • To determine if specific TLR4 variants lead to defective immune responses in airway epithelial cells and peripheral blood mononuclear cells (PBMCs).

Main Methods:

  • Human bronchial epithelial cells were transfected with TLR4 constructs representing common ((299)Asp/(399)Thr) and variant ((299)Gly or (399)Ile) alleles.
  • Cells were challenged with RSV in vitro to analyze cytokine production and TLR4 translocation.
  • RSV-induced responses in PBMCs from children with corresponding TLR4 genotypes were compared.

Main Results:

  • Bronchial epithelial cells with (299)Gly or (399)Ile TLR4 variants showed reduced cell surface translocation of TLR4.
  • These cells exhibited impaired NF-kappaB signaling and produced lower levels of key cytokines (IFNs, IL-8, IL-10, IL-12p35, IL-18, CCL8) and lacked TNF-alpha.
  • Children with these TLR4 variants displayed blunted PBMC responses to RSV.

Conclusions:

  • The (299)Gly and (399)Ile TLR4 variants are associated with defective innate immune responses at the airway epithelial level.
  • This compromised first-line defense may contribute to increased susceptibility to severe RSV infections in children carrying these TLR4 variants.

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