Department of Pediatrics, University of Texas Medical Branch, Galveston, Texas, United States of America.
PLoS One. 2013 Oct 29;8(10):e78849. doi: 10.1371/journal.pone.0078849. eCollection 2013.
Human metapneumovirus (hMPV) is one of the main causes of acute respiratory tract infections in children, elderly and immunocompromised patients. The mammalian Toll-like receptors (TLR) were identified as critical regulators of innate immunity to a variety of microbes, including viruses. We have recently shown that hMPV-induced cytokine, chemokine and type I interferon secretion in dendritic cells occurs via TLR4, however, its role in hMPV-induced disease is unknown. In this study, wild-type(WT) and TLR4-deficient mice (TLR4⁻/⁻) were infected with hMPV and examined for clinical disease parameters, such as body weight loss and airway obstruction, viral clearance, lung inflammation, dendritic cell maturation, T-cell proliferation and antibody production. Our results demonstrate that absence of TLR4 in hMPV-infected mice significantly reduced the inflammatory response as well as disease severity, shown by reduced body weight loss and airway obstruction and hyperresponsiveness (AHR), compared to WT mice. Levels of cytokines and chemokines were also significantly lower in the TLR4⁻/⁻ mice. Accordingly, recruitment of inflammatory cells in the BAL, lungs, as well as in lymph nodes, was significantly reduced in the TLR4⁻/⁻ mice, however, viral replication and clearance, as well as T-cell proliferation and neutralizing antibody production, were not affected. Our findings indicate that TLR4 is important for the activation of the innate immune response to hMPV, however it does play a role in disease pathogenesis, as lack of TLR4 expression is associated with reduced clinical manifestations of hMPV disease, without affecting viral protection.
人偏肺病毒（hMPV）是导致儿童、老年人和免疫功能低下者急性呼吸道感染的主要病原体之一。哺乳动物 Toll 样受体（TLR）被鉴定为先天免疫多种微生物（包括病毒）的关键调节剂。我们最近表明，hMPV 在树突状细胞中诱导细胞因子、趋化因子和 I 型干扰素的分泌是通过 TLR4 发生的，然而，其在 hMPV 诱导疾病中的作用尚不清楚。在这项研究中，野生型（WT）和 TLR4 缺陷型（TLR4⁻/⁻）小鼠感染 hMPV，并检查临床疾病参数，如体重减轻和气道阻塞、病毒清除、肺部炎症、树突状细胞成熟、T 细胞增殖和抗体产生。我们的结果表明，TLR4 在 hMPV 感染小鼠中的缺失显著降低了炎症反应和疾病严重程度，与 WT 小鼠相比，体重减轻和气道阻塞以及高反应性（AHR）减少。TLR4⁻/⁻小鼠中的细胞因子和趋化因子水平也显著降低。因此，TLR4⁻/⁻小鼠中 BAL、肺和淋巴结中的炎症细胞募集显著减少，然而，病毒复制和清除以及 T 细胞增殖和中和抗体产生不受影响。我们的研究结果表明，TLR4 对于 hMPV 先天免疫反应的激活很重要，但它在疾病发病机制中不起作用，因为缺乏 TLR4 表达与 hMPV 疾病的临床表现减少有关，而不影响病毒保护。
