The TLR3/IRF1/Type III IFN Axis Facilitates Antiviral Responses against Enterovirus Infections in the Intestine.
The TLR3/IRF1/Type III IFN Axis Facilitates Antiviral Responses against Enterovirus Infections in the Intestine.
复制标题
TLR3/IRF1/III 型 IFN 轴促进肠道内针对肠道病毒感染的抗病毒反应。
作者：
Su R;Shereen MA;Zeng X;Liang Y;Li W;Ruan Z;Li Y;Liu W;Liu Y;Wu K;Luo Z;Wu J
肠道病毒感染是世界范围内人类疾病和公共卫生风险的重要来源，但对病毒复制过程中宿主肠道上皮细胞表面的先天免疫反应机制知之甚少。我们报道了肠道病毒71型感染后培养的人正常细胞和癌细胞(IECS)、小鼠组织和人类临床肠道标本的上皮免疫反应。结果从机制上揭示了在肠道病毒包括肠道病毒71型(EV71)、柯萨奇病毒B3型(CVB3)和脊髓灰质炎病毒1型(PV1)感染时，通过TLR3/λ信号转导产生的主要干扰素是III型干扰素(干扰素-λ1和干扰素IRF2/3)，而不是I型干扰素(干扰素-α和干扰素-β)。随后，干扰素-λ在体内外诱导了抗肠病毒复制的活性。这些研究揭示了宿主肠道中参与TLR3/IRF1途径的III型干扰素产生的新过程在肠道病毒感染中的作用，这突显了肠道病毒感染过程中肠道抗病毒防御的调节方式。肠道病毒感染胃肠道上皮细胞，引起多种人类疾病，在全球范围内构成公共卫生风险。然而，肠道黏膜对早期肠道病毒感染的宿主免疫反应的机制仍然不清楚。在这里，我们发现人类肠道病毒，包括肠道病毒71型、柯萨奇病毒B3型和脊髓灰质炎病毒1型，在培养的人正常和癌变的肠上皮细胞、小鼠肠道组织和人类临床肠道标本中，主要诱生III型干扰素(干扰素-λ1和干扰素λ2/3)，而不是I型干扰素(干扰素-α和干扰素-β)。机制研究表明，肠道病毒感染可通过Toll样受体3/干扰素调节因子1(TLR3/IRF1)信号通路诱导肠内皮细胞产生干扰素-λ。反过来，补充干扰素-λ随后诱导针对肠道病毒复制的内在抗病毒反应。值得注意的是，在新生C57BL/6J小鼠体内注射重组干扰素-λ2蛋白可抑制EV71复制并保护小鼠免受病毒致死效应。综上所述，这些结果揭示了宿主通过激活TLR3/IRF1/III型干扰素轴而在肠道内诱导针对肠道病毒感染的免疫应答的独特机制。这一新发现将为预防和治疗肠道病毒感染和相关疾病提供一种抗病毒策略。
Enterovirus infections are significant sources of human diseases and public health risks worldwide, but little is known about the mechanism of innate immune response in host intestine epithelial surface during the viral replication. We reported the epithelial immune response in cultured human normal and cancerous cells (IECs), mouse tissues, and human clinical intestine specimens following infection with enterovirus 71. The results mechanistically revealed type III interferons (IFN-λ1 and IFN-λ2/3), rather than type I interferons (IFN-α and IFN-β), as the dominant production through TLR3/IRF1 signaling upon multiple human enterovirus infection, including enterovirus 71 (EV71), coxsackievirus B3 (CVB3), and poliovirus 1 (PV1). IFN-λ subsequently induced antiviral activity against enterovirus replication in vitro and in vivo. These studies uncovered the role of the novel process of type III IFN production involved in the TLR3/IRF1 pathway in host intestine upon enterovirus infection, which highlighted a regulatory manner of antiviral defense in intestine during enterovirus infection. Enteroviruses infect gastrointestinal epithelium cells, cause multiple human diseases, and present public health risks worldwide. However, the mechanisms underlying host immune responses in intestinal mucosa against the early enterovirus infections remain elusive. Here, we showed that human enteroviruses including enterovirus 71 (EV71), coxsackievirus B3 (CVB3), and poliovirus 1 (PV1) predominantly induce type III interferons (IFN-λ1 and IFN-λ2/3), rather than type I interferons (IFN-α and IFN-β), in cultured human normal and cancerous intestine epithelial cells (IECs), mouse intestine tissues, and human clinical intestine specimens. Mechanistic studies demonstrated that IFN-λ production is induced upon enterovirus infection through the Toll-like receptor 3/interferon regulatory factor 1 (TLR3/IRF1) signaling pathway in IECs. In turn, the supplementation of IFN-λ subsequently induces intrinsically antiviral responses against enterovirus replication. Notably, intraperitoneal injection in neonatal C57BL/6J mice with mouse recombinant IFN-λ2 protein represses EV71 replication and protects mice from viral lethal effects. Altogether, these results revealed a distinct mechanism by which the host elicited immune responses against enterovirus infections in intestine through activating the TLR3/IRF1/type III IFN axis. The new findings would provide an antiviral strategy for the prevention and treatment of enterovirus infections and associated diseases.