Toll-Like Receptor 3 Signaling via TRIF Contributes to a Protective Innate Immune Response to Severe Acute Respiratory Syndrome Coronavirus Infection.
Toll-Like Receptor 3 Signaling via TRIF Contributes to a Protective Innate Immune Response to Severe Acute Respiratory Syndrome Coronavirus Infection.
复制标题
DOI：
10.1128/mbio.00638-15
复制
发表时间：
2015-05-26
期刊：
影响因子：
6.4
通讯作者：
Baric RS
中科院分区：
文献类型：
--
作者：
Totura AL;Whitmore A;Agnihothram S;Schäfer A;Katze MG;Heise MT;Baric RS
Toll样受体是一种传感器，可以识别病毒、细菌和真菌的分子模式，启动对入侵病原体的先天免疫反应。高致病性冠状病毒严重急性呼吸综合征冠状病毒(SARS-CoV)和中东呼吸综合征冠状病毒(MERS-CoV)的出现是全球公共卫生关注的问题，因为缺乏有效的疫苗平台和抗病毒治疗策略。此前，已有研究表明，MyD88是体内小鼠适应的SARS-CoV感染的先天免疫反应的必要组成部分，是多个TLR信号传递所必需的适配器蛋白。在这里，我们证明了TLR3−/−、TLR4−/−和TRAM−/−小鼠比野生型小鼠更容易感染SARS冠状病毒，但只经历了短暂的体重减轻，没有因感染而死亡。相比之下，缺乏TLR3/TLR4适配器TRIF的小鼠对SARS-CoV感染高度敏感，表现出体重减轻、死亡率增加、肺功能降低、肺病理增加和病毒滴度增加。感染SARS-CoV的TRIF−/−小鼠出现明显的炎症变化，包括中性粒细胞和炎性细胞类型的过度渗透，这与其他已知的急性呼吸窘迫综合征(ARDS)原因(包括流感病毒感染)的病理增加有关。在感染TRIF−/−小鼠后，也发现了异常的促炎细胞因子、趋化因子和干扰素刺激基因信号程序，这与感染SARS冠状病毒或MERS冠状病毒后疾病转归较差的人类患者相似。这些发现突显了TLR适配器信号在产生对高致病性冠状病毒感染的平衡保护性先天免疫反应中的重要性。Toll样受体是一种感受器蛋白家族，使免疫系统能够区分“自我”和“非自我”。TLRs的激动剂和拮抗剂已被认为可用作疫苗佐剂或抗病毒化合物。在过去的15年里，高致病性冠状病毒SARS-CoV和MERS-CoV的出现在人类人群中造成了严重的疾病并伴随着高死亡率，但目前还没有被批准的治疗方法或疫苗。在这里，我们证明了TLR信号通过TRIF接头蛋白保护小鼠免受致命的SARS-CoV疾病的侵袭。我们的发现表明，通过TRIF驱动和MyD88驱动的途径进行的平衡免疫反应可能为严重的SARS-CoV疾病提供最有效的宿主细胞内在抗病毒防御反应，而在我们的小鼠模型中，去除TLR信号的任何一个分支都会导致致命性的SARS-CoV疾病。这些数据应该为TLR激动剂和拮抗剂在冠状病毒特异性疫苗和抗病毒策略中的设计和使用提供信息。
Toll-like receptors (TLRs) are sensors that recognize molecular patterns from viruses, bacteria, and fungi to initiate innate immune responses to invading pathogens. The emergence of highly pathogenic coronaviruses severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) is a concern for global public health, as there is a lack of efficacious vaccine platforms and antiviral therapeutic strategies. Previously, it was shown that MyD88, an adaptor protein necessary for signaling by multiple TLRs, is a required component of the innate immune response to mouse-adapted SARS-CoV infection in vivo. Here, we demonstrate that TLR3−/−, TLR4−/−, and TRAM−/− mice are more susceptible to SARS-CoV than wild-type mice but experience only transient weight loss with no mortality in response to infection. In contrast, mice deficient in the TLR3/TLR4 adaptor TRIF are highly susceptible to SARS-CoV infection, showing increased weight loss, mortality, reduced lung function, increased lung pathology, and higher viral titers. Distinct alterations in inflammation were present in TRIF−/− mice infected with SARS-CoV, including excess infiltration of neutrophils and inflammatory cell types that correlate with increased pathology of other known causes of acute respiratory distress syndrome (ARDS), including influenza virus infections. Aberrant proinflammatory cytokine, chemokine, and interferon-stimulated gene (ISG) signaling programs were also noted following infection of TRIF−/− mice that were similar to those seen in human patients with poor disease outcome following SARS-CoV or MERS-CoV infection. These findings highlight the importance of TLR adaptor signaling in generating a balanced protective innate immune response to highly pathogenic coronavirus infections. Toll-like receptors are a family of sensor proteins that enable the immune system to differentiate between “self” and “non-self.” Agonists and antagonists of TLRs have been proposed to have utility as vaccine adjuvants or antiviral compounds. In the last 15 years, the emergence of highly pathogenic coronaviruses SARS-CoV and MERS-CoV has caused significant disease accompanied by high mortality rates in human populations, but no approved therapeutic treatments or vaccines currently exist. Here, we demonstrate that TLR signaling through the TRIF adaptor protein protects mice from lethal SARS-CoV disease. Our findings indicate that a balanced immune response operating through both TRIF-driven and MyD88-driven pathways likely provides the most effective host cell intrinsic antiviral defense responses to severe SARS-CoV disease, while removal of either branch of TLR signaling causes lethal SARS-CoV disease in our mouse model. These data should inform the design and use of TLR agonists and antagonists in coronavirus-specific vaccine and antiviral strategies.