Tulic Meri K, Hurrelbrink Robert J, Prêle Cecilia M, Laing Ingrid A, Upham John W, Le Souef Peter, Sly Peter D, Holt Patrick G
Division of Cell Biology, Telethon Institute for Child Health Research, Centre for Child Health Research, University of Western Australia, West Perth, WA 6872, Australia.
J Immunol. 2007 Jul 1;179(1):132-40. doi: 10.4049/jimmunol.179.1.132.
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 (299)Gly and (399)Ile 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 ((299)Asp/(399)Thr), or the (299)Gly or (399)Ile 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 (299)Gly or (399)Ile displayed normal levels of intracellular TLR4 but failed to efficiently translocate the receptor to the cell surface. This was associated with reduced NF-kappaB 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-alpha. 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.
呼吸道合胞病毒（RSV）感染后发生的严重细支气管炎仅出现在一小部分受感染的婴儿中，疾病严重程度存在差异的原因尚不清楚。对RSV的先天免疫反应由TLR-4介导，TLR4基因的（299）Gly和（399）Ile等位基因在流行病学上与儿童RSV疾病严重程度增加有关。我们推测，相对于通过受体常见形式介导的反应，由这些受体变体形式介导的对RSV的细胞免疫反应存在缺陷。用编码常见TLR4基因序列（（299）Asp/（399）Thr）、（299）Gly或（399）Ile等位基因的TLR4构建体转染人支气管上皮细胞，并分析不同转染细胞对体外RSV攻击的细胞因子反应。后续研究比较了表达这些相同TLR4基因型的儿童外周血单核细胞（PBMC）中RSV诱导的反应。表达（299）Gly或（399）Ile的人支气管上皮细胞内TLR4水平正常，但未能有效地将受体转运到细胞表面。这与TLR4激活后NF-κB信号传导减少、IFN、IL-8、IL-10、IL-12p35、IL-18和CCL8产生减少以及急性期TNF-α缺失有关。表达相同TLR4变体的儿童PBMC对RSV的反应减弱也反映了这些发现。因此，表达这些TLR4变体的儿童气道上皮表面对RSV的一线防御受损可能会增加对这种病毒严重感染的易感性。
