病毒引起的感染症每年都造成嚴重的發病率和致死率。病毒分子與宿主分子都會影響病毒感染的結果，此現象特別發生於嚴重的病毒感染，例如:禽流感病毒導致異常的發炎反應，產生過多的發炎激素，但較少的第一型干擾素。先天免疫系統不但提供第一道防線且可以進一步調控適應性免疫對抗病毒，因此了解先天免疫系統如何對抗病毒至關重要。第一型干擾素是病毒感染的細胞在早期所分泌關鍵的細胞激素，可以進一步活化抗病毒的先天免疫反應。Toll-like receptors（TLRs），細胞質RIG-I-like receptors（RLRs）和DNA sensors都可以偵測病毒核酸並活化第一型干擾素以對抗病毒感染，但連結RLRs偵測病毒到活化抗病毒反應的機制仍待更進一步的研究。TBK-1已知參與TLR3, TLR4, RLRs 及DNA sensor活化第一型干擾素。我們先前發現一個新的先天免疫調節分子稱為TAPE (TBK1-Associated Protein in Endolysosomes)，也稱為CC2D1A/Freud-1/Aki-1。TAPE參與TLR3和TLR4活化第一型干擾素的路徑，此外從我們先前的研究結果發現TAPE在哺乳類細胞也參與RLRs活化第一型干擾素。因為這些原因，我對於利用遺傳學方法研究TAPE於調節RIG-I like receptor的角色感到興趣，並研究其調控的機制。另一方面，腸病毒71型是一個主要引起手足口症和神經系統疾病的病毒，但我們對於腸病毒71型引起的致病機制仍然不夠了解。最近的文獻顯示腸病毒71型和先天免疫系統之間的相互作用仍相當複雜。先天免疫系統如何偵測腸病毒71型感染並活化第一型干擾素對抗病毒免疫仍有待進一步研究。因此，我的工作著重在三個目標: (1) 活體外及活體實驗探討TAPE在先天免疫對抗RNA病毒感染所扮演的角色。(2) 探討TAPE如何調控RLR路徑的機制。(3) 探討先天免疫受體偵測腸病毒71型。關於目標1及目標2的研究，我們已經產生TAPE基因剔除小鼠及TAPE基因條件性剔除小鼠來研究TAPE基因的角色。在活體外實驗，以RLR ligand 刺激，TAPE 基因剔除的小鼠胚胎纖維母細胞及胎兒肝臟巨噬細胞後所表現的細胞激素降低。於流感病毒感染後，TAPE條件性剔除小鼠的死亡率比野生型(wild type)高。另外，以共軛焦顯微鏡觀察所得的結果發現，RLR ligand刺激後，RIG-I在細胞內的位置與TAPE重疊，而且移到含有 TAPE 及Rab5的內涵體(endosomes)，因此早期內涵體可能參與RIG-I相關的活化訊息路徑。綜合以上活體和生化實驗的結果，我們認為TAPE參與RIG-I活化第一型干擾素以對抗病毒的重要性。關於目標3的研究，我們一開始篩選幾個RNA sensor (RIG-I, MDA5 及TLR3)參與偵測腸病毒71型活化第一型干擾素。值得注意的是，表達TLR3的HEK293細胞可以偵測腸病毒71型感染並活化第一型干擾素媒介的抗病毒反應，而TLR3基因沉默於小鼠及人類的初代免疫細胞會降低腸病毒71型活化第一型干擾素。我們的結果也顯示腸病毒71型會造成TLR3的蛋白表達下降，腸病毒71型會利用2A蛋白酶降低TLR3的蛋白表達。綜合目標3的結果，我們不只證明TLR3對於腸病毒71型感染的重要性，此外也揭示腸病毒71型蛋白酶2A會影響TLR3而躲避先天免疫防禦的現象。

Viral infections cause the severe morbidity and mortality of humans worldwide every year. Both viral and host factors contribute to the outcome of viral infection. Particularly, severe viral infections like avian influenza viruses often lead to aberrant inflammatory responses, which are manifested by excessive inflammatory cytokines but lower expression of type I interferons (IFNs). Thus, it is crucial to better understand how the host innate immune system interacts with viruses because the host innate immune system serves the first line of host defenses and also coordinates the following adaptive immune responses to viral infection. Type I IFNs are key cytokines secreted from infected cells for triggering antiviral innate immunity at the early viral infection. Endosomal Toll-like receptors (TLRs), cytosolic RIG-I-like receptors (RLRs) and DNA sensors function to detect viral nucleic acids to trigger type I IFN antiviral responses. The underlying mechanisms linking RLR-mediated viral recognition to antiviral immunity remain to be further explored. TBK1 is a key protein kinase linking TLR3, TLR4, RLRs and DNA sensors to type I IFN activation. Through our previous work, we uncovered an innate immune regulator termed TAPE (TBK1-Associated Protein in Endolysosomes), also known as CC2D1A/Freud-1/Aki-1. TAPE is critical for linking the TLR3 and TLR4 pathways to type I interferon induction. Further, previous findings from our lab showed that TAPE was involved in RLRs-mediated IFN-β promoter induction in mammalian cells. Given these facts, I was interested in exploring whether TAPE plays a critical role in regulating the RIG-I like receptor pathways by genetic approaches and then investigating the mechanisms of this regulation. In addition, Enterovirus 71 (EV71) has emerged as a major pathogen causing the hand, foot and mouth disease and neurological disorders. The pathogenesis of these EV71-mediated diseases is still poorly understood. Recent evidence reveals an intricate interplay between EV71 and the innate immune system. Yet, the mechanisms of how the innate immune system detects EV71 infection to elicit type I interferon (IFN)-mediated antiviral immunity are still not fully understood. My thesis work focuses on three aims: (1) Aim 1 is to assess ex vivo and in vivo functions of TAPE in antiviral innate immunity during RNA virus infection. (2) Aim 2 is to explore molecular mechanisms of how TAPE regulates the RLR pathways. (3) Aim 3 is to study the innate immune recognition of enterovirus 71 infection. Regarding the Aim 1 and Aim 2 studies, TAPE-direct and conditional knockout mice have been generated for my study purpose. Results from ex vivo study showed that TAPE-deficient mouse embryonic fibroblasts (MEFs) and fetal liver macrophages were defective in cytokine production upon RLR ligand stimulation. In addition, TAPE conditional knockout mice exhibited a more severe mortality than wild type mice upon influenza A virus (IAV) infection. Confocal microscopic results showed that RIG-I was colocalized with TAPE after RLR ligand stimulation. Furthermore, our results showed that RIG-I was co-localized with an endosomal marker Rab5 and TAPE after RLR ligand stimulation, suggesting that early endosomes are involved in RIG-I signaling. Together, our in vivo and biochemical results suggest a crucial role for TAPE in linking the RIG-I pathway to type I IFN-mediated antiviral responses. Regarding the Aim 3 study, we first screened several viral RNA sensors, including TLR3, RIG-I and MDA5, for detecting EV71 infection to trigger type I IFN production. Of note, ectopic expression of TLR3 in HEK293 cells conferred the detection of EV71 infection to induce type-I IFN-mediated antiviral responses. Silencing of TLR3 in mouse and human primary immune cells impaired the activation of IFN-β upon EV71 infection. Our results also demonstrated that TLR3 was a target of EV71 infection. EV71 protease 2A was implicated in the downregulation of the TLR3 protein level on the post-transcriptional level. Together, our results not only demonstrate the importance of the TLR3 pathway in response to EV71 infection but also reveal the involvement of EV71 protease 2A in subverting innate immune defenses by targeting TLR3.

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