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TLR4 Polymorphisms Mediate Impaired Responses to Respiratory Syncytial Virus and Lipopolysaccharide¹

Meri K. Tulic^*, Robert J. Hurrelbrink, Cecilia M. Prêle, Ingrid A. Laing^*,¶, John W. Upham^*, Peter Le Souef^¶, Peter D. Sly and Patrick G. Holt^2,*

^* Division of Cell Biology, Division of Virology, Division of Molecular Biotechnology, and Division of Clinical Sciences, Telethon Institute for Child Health Research, Centre for Child Health Research, and ^¶ School of Paediatrics and Child Health, University of Western Australia, Perth, Australia

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-B 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-. 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the National Health and Medical Research Council (NH&MRC) of Australia. M.K.T. was supported by the NH&MRC Peter Doherty Fellowship; P.D.S. and P.G.H. are Senior Principal Research Fellows of the NH&MRC, Australia. I.A.L. was supported by the Australian Respiratory Council Ann Woolcock Research Fellowship.

² Address correspondence and reprint requests to Prof. Patrick G. Holt, Division of Cell Biology, Telethon Institute for Child Health Research, P.O. Box 855, West Perth, WA 6872, Australia. E-mail address: patrick{at}ichr.uwa.edu.au

³ Abbreviations used in this paper: RSV, respiratory syncytial virus; HBE, human bronchial epithelial; TCID₅₀, 50% tissue culture-infective dose; MxA, myxovirus protein A.