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 Tlr4 mutant (C3H/HeJ, HeJ, Tlr4Lps-d) and its wild-type (C3H/HeOuJ, OuJ, Tlr4Lps-n) mice and five genetically diverse, differentially responsive strains bearing the wild-type Tlr4Lps-n 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 (Cxcl3, Saa1) and heat shock protein (Hspa1a, Hsph1) 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 (Oasl1, Irg1, Mx1) and epidermal differentiation complex (Krt4, Lce3a) 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 Tlr4-wild-type strains provide new insights into the mechanism of RSV disease and potential therapeutic targets.

中文翻译：

---

Toll样受体4介导的呼吸道合胞病毒疾病和差异易感近交小鼠品系的肺转录组学。

呼吸道合胞病毒（RSV）在婴儿，幼儿和易感成年人中引起严重的下呼吸道疾病。尽管已知与Toll样受体4（TLR4）相关的先天免疫反应起作用，但尚未完全了解RSV疾病的发病机理。本研究旨在确定TLR4介导的疾病表型和肺转录组学，并阐明小鼠自交系中差异RSV敏感性的转录机制。显性阴性Tlr4突变体（C3H / HeJ，HeJ，Tlr4Lps-d）及其野生型（C3H / HeOuJ，OuJ，Tlr4Lps-n）小鼠和5个带有野生型Tlr4Lps-n等位基因的遗传差异反应性菌株。感染了RSV。支气管肺泡灌洗，组织病理学和全基因组转录组学被用来表征对RSV的肺反应。与OuJ小鼠相比，HeJ中RSV诱导的肺中性粒细胞增多[感染后1天（pi）]，上皮增殖（pi 1天）和淋巴细胞浸润（pi 5天）显着降低。在HeJ中，肺RSV表达也比在OuJ中显着受到抑制。免疫/炎症（Cxcl3，Saa1）和热休克蛋白（Hspa1a，Hsph1）基因的上调是OuJ小鼠的特征，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。菌株特异性转录组学表明，病毒应答（Oasl1，Irg1，Mx1）和表皮分化复合体（Krt4，Lce3a）基因可能有助于在包括C57BL / 6J在内的耐药菌株中对RSV的TLR4独立防御。数据表明TLR4有助于肺部RSV的发病机理和细胞免疫的激活，炎性体复合物，血管损伤是其基础。差异反应Tlr4野生型菌株中不同的转录组学为RSV疾病的机制和潜在的治疗靶点提供了新的见识。