Type I Interferons Triggered through the Toll-Like Receptor 3–TRIF Pathway Control Coxsackievirus A16 Infection in Young Mice
Type I Interferons Triggered through the Toll-Like Receptor 3–TRIF Pathway Control Coxsackievirus A16 Infection in Young Mice
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DOI：
10.1128/jvi.01627-15
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发表时间：
2015-08
影响因子：
5.4
通讯作者：
Juhao Yang;Chunfu Yang;Nining Guo;Kai Zhu;K. Luo;N. Zhang;Hui Zhao;Ying Cui;Lei Chen;
中科院分区：
文献类型：
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作者：
Juhao Yang;Chunfu Yang;Nining Guo;Kai Zhu;K. Luo;N. Zhang;Hui Zhao;Ying Cui;Lei Chen;
【摘要】：柯萨奇病毒A16(CVA16)是儿童手足口病(HFMD)的主要病原体之一。宿主针对 CVA16 感染的防御机制仍然几乎完全未知。与之前对肠道病毒 71 (EV71) 感染的观察不同，我们在此表明，γ 干扰素 (IFN-γ) 或恒定 NK T 细胞缺陷不会影响 CVA16 感染小鼠的疾病发展或存活。相比之下，I型干扰素受体缺陷导致小鼠出现更严重的疾病，并且小鼠的存活率比野生型小鼠更低。同样，Toll 样受体 3 (TLR3) 和 TRIF 的缺陷（而非其他模式识别受体）导致 CVA16 感染小鼠的存活率下降。 TLR3-TRIF 信号传导对于小鼠 CVA16 感染过程中 I 型干扰素的诱导是必不可少的，并保护年轻小鼠免受感染引起的疾病。特别是，TRIF 介导的免疫对于在疾病发生之前防止神经元系统中的 CVA16 复制至关重要。还发现 IFN-β 治疗可以补偿小鼠 TRIF 缺陷，并降低 CVA16 感染小鼠的疾病严重程度和死亡率。总而言之，TLR3-TRIF 信号传导诱导的 I 型干扰素介导针对 CVA16 感染的保护性免疫。这些发现可能有助于揭示对抗 CVA16 感染引起的手足口病的治疗策略。重要性 手足口病（HFMD）是亚太地区公共卫生的主要威胁。 CVA16 和 EV71 都是导致手足口病的主要病原体。大多数研究工作都集中在毒性更强的 EV71 上，但对 CVA16 的研究却很少。迄今为止，宿主对 CVA16 感染的免疫反应尚未阐明。本研究发现了宿主针对 CVA16 感染的保护性免疫的初步分子机制，首次解释了为什么 CVA16 和 EV71 在感染人类时会导致不同的临床结果。因此，应对这两种病毒引起的手足口病病例制定不同的治疗策略。
ABSTRACT Coxsackievirus A16 (CVA16) is one of the major etiological agents of hand, foot, and mouth disease (HFMD) in children. The host defense mechanisms against CVA16 infection remain almost entirely unknown. Unlike previous observations with enterovirus 71 (EV71) infection, here we show that gamma interferon (IFN-γ) or invariant NK T cell deficiency does not affect disease development or the survival of CVA16-infected mice. In contrast, type I interferon receptor deficiency resulted in the development of more severe disease in mice, and the mice had a lower survival rate than wild-type mice. Similarly, a deficiency of Toll-like receptor 3 (TLR3) and TRIF, but not other pattern recognition receptors, led to the decreased survival of CVA16-infected mice. TLR3-TRIF signaling was indispensable for the induction of type I interferons during CVA16 infection in mice and protected young mice from disease caused by the infection. In particular, TRIF-mediated immunity was critical for preventing CVA16 replication in the neuronal system before disease occurred. IFN-β treatment was also found to compensate for TRIF deficiency in mice and decreased the disease severity in and mortality of CVA16-infected mice. Altogether, type I interferons induced by TLR3-TRIF signaling mediate protective immunity against CVA16 infection. These findings may shed light on therapeutic strategies to combat HFMD caused by CVA16 infection. IMPORTANCE Hand, foot, and mouth disease (HFMD) is a major threat to public health in the Asia-Pacific region. Both CVA16 and EV71 are major pathogens that are responsible for HFMD. The majority of research efforts have focused on the more virulent EV71, but little has been done with CVA16. Thus far, host immune responses to CVA16 infection have not yet been elucidated. The present study discovered an initial molecular mechanism underlying host protective immunity against CVA16 infection, providing the first explanation for why CVA16 and EV71 cause different clinical outcomes upon infection of humans. Therefore, different therapeutic strategies should be developed to treat HFMD cases caused by these two viruses.