Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina.
Curriculum in Toxicology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Physiol Genomics. 2019 Dec 1;51(12):630-643. doi: 10.1152/physiolgenomics.00101.2019. Epub 2019 Nov 18.
Respiratory syncytial virus (RSV) causes severe lower respiratory tract disease in infants, young children, and susceptible adults. The pathogenesis of RSV disease is not fully understood, although toll-like receptor 4 (TLR4)-related innate immune response is known to play a role. The present study was designed to determine TLR4-mediated disease phenotypes and lung transcriptomics and to elucidate transcriptional mechanisms underlying differential RSV susceptibility in inbred strains of mice. Dominant negative mutant (C3H/HeJ, HeJ, ) and its wild-type (C3H/HeOuJ, OuJ, ) mice and five genetically diverse, differentially responsive strains bearing the wild-type allele were infected with RSV. Bronchoalveolar lavage, histopathology, and genome-wide transcriptomics were used to characterize the pulmonary response to RSV. RSV-induced lung neutrophilia [1 day postinfection (pi)], epithelial proliferation (1 day pi), and lymphocytic infiltration (5 days pi) were significantly lower in HeJ compared with OuJ mice. Pulmonary RSV expression was also significantly suppressed in HeJ than in OuJ. Upregulation of immune/inflammatory (, ) and heat shock protein (, ) genes was characteristic of OuJ mice, while cell cycle and cell death/survival genes were modulated in HeJ mice following RSV infection. Strain-specific transcriptomics suggested virus-responsive (, , ) and epidermal differentiation complex (, ) genes may contribute to TLR4-independent defense against RSV in resistant strains including C57BL/6J. The data indicate that TLR4 contributes to pulmonary RSV pathogenesis and activation of cellular immunity, the inflammasome complex, and vascular damage underlies it. Distinct transcriptomics in differentially responsive -wild-type strains provide new insights into the mechanism of RSV disease and potential therapeutic targets.
呼吸道合胞病毒 (RSV) 可导致婴儿、幼儿和易感成年人发生严重的下呼吸道疾病。RSV 疾病的发病机制尚未完全阐明，尽管已知 Toll 样受体 4 (TLR4) 相关的先天免疫反应发挥了作用。本研究旨在确定 TLR4 介导的疾病表型和肺部转录组学，并阐明导致近交系小鼠对 RSV 易感性差异的转录机制。 显性负突变体 (C3H/HeJ，HeJ， ) 和其野生型 (C3H/HeOuJ，OuJ， ) 小鼠以及携带野生型 等位基因的五个遗传上不同、反应不同的品系被 RSV 感染。使用支气管肺泡灌洗、组织病理学和全基因组转录组学来表征对 RSV 的肺部反应。与 OuJ 小鼠相比，HeJ 小鼠的 RSV 诱导的肺中性粒细胞增多症 [感染后 1 天 (pi)]、上皮细胞增殖 (1 pi) 和淋巴细胞浸润 (5 pi) 显著降低。HeJ 中的肺部 RSV 表达也明显低于 OuJ。OuJ 小鼠的免疫/炎症 (, ) 和热休克蛋白 (, ) 基因上调，而 RSV 感染后 HeJ 小鼠的细胞周期和细胞死亡/存活基因受到调节。品系特异性转录组学表明，病毒反应性 (,, ) 和表皮分化复合物 (, ) 基因可能有助于包括 C57BL/6J 在内的抗性品系对 RSV 的 TLR4 非依赖性防御。数据表明，TLR4 有助于肺部 RSV 发病机制和细胞免疫的激活，其炎症小体复合物和血管损伤是其基础。不同反应性 -野生型品系的转录组学提供了 RSV 疾病机制和潜在治疗靶点的新见解。
