TLR4 Polymorphisms Mediate Impaired Responses to Respiratory Syncytial Virus and Lipopolysaccharide1

Tulic, Meri K., Hurrelbrink, Robert j,, Prele, Cecilia M., Laing, Ingrid A,, Upham, John W., Le Souef, Peter, Sly, Peter D. and Holt, Patrick G. (2007) TLR4 Polymorphisms Mediate Impaired Responses to Respiratory Syncytial Virus and Lipopolysaccharide1. Journal of Immunology, 179 1: 132-140.

Author Tulic, Meri K.
Hurrelbrink, Robert j,
Prele, Cecilia M.
Laing, Ingrid A,
Upham, John W.
Le Souef, Peter
Sly, Peter D.
Holt, Patrick G.
Title TLR4 Polymorphisms Mediate Impaired Responses to Respiratory Syncytial Virus and Lipopolysaccharide1
Journal name Journal of Immunology   Check publisher's open access policy
ISSN 0022-1767
Publication date 2007-07
Sub-type Article (original research)
Volume 179
Issue 1
Start page 132
End page 140
Total pages 9
Place of publication Bethesda, MD, U.S.A.
Publisher American Association of Immunologists
Language eng
Subject 110704 Cellular Immunology
110701 Allergy
Formatted 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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
ERA 2012 Admin Only
School of Medicine Publications
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