A型流感病毒（IAV）是引起人類和其他物種呼吸道疾病的主要病原體。已知幾種RNA感應器，包括細胞質RIG-I和內體Toll樣受體3（TLR3）和TLR7，參與檢測IAV RNA以觸發I型乾擾素（IFN）介導的抗病毒免疫。同時，IAV採用多種策略來逃避宿主細胞中的抗病毒防禦以成功複製。例如，IAV非結構蛋白1（NS1）顯示通過與RIG-I競爭結合病毒RNA來干擾RIG-I感知。我們對於IAV NS1是否有其他躲避宿主抗病毒免疫反應的方式感興趣。我們實驗室以前的研究揭示了NS1 藉由新的非RNA結合機制來逃脫免疫反應。NS1使用其TRAF3結合基序（TIM）結合E3泛素連接酶TRAF3以阻斷RIG-I信號傳導以進行IFN誘導。除了RIG-I外，還顯示TRAF3連接TLR3和TLR7與I型IFN誘導。鑑於這些事實，我的論文工作集中在以下目標：（1）進一步研究在常規樹突狀細胞（cDC）中IAV NS1拮抗RIG-I信號傳導中的功能作用。 （2）進一步研究NS1是否可能干擾TLR3和TLR7等其他RNA傳感途徑。（3）目進一步闡明IAV NS1 TIM突變病毒在IAV感染期間的體內作用。我們的離體研究表明，在感染期間，攜帶TIM突變的IAV NS1突變病毒與IAV WT病毒相比在cDC誘導了更高的IFN-β產生。此外，IAV NS1 TIM突變體比較無法阻斷TLR3-TRIF-TRAF3和TLR7途徑對I型IFN誘導。體內結果顯示，與IAV WT病毒相比，感染IAV NS1 TIM突變病毒的小鼠有更好的存活率。此外，IAV NS1 TIM突變體病毒在感染的早期階段在小鼠肺中誘導更高的I型IFN產生。有趣的是，我們的疫苗接種實驗表明，IAV NS1 TIM突變病毒的刺激提供保護力針對致死劑量的WT病毒感染。總之，我們的數據表明，IAV NS1通過以不依賴RNA結合的方式結合TRAF3並抵消多種RNA傳感途徑來達到抵抗宿主抗病毒免疫。我們的實驗室發表的研究表明，TBK1-associated protein in endolysosomes（TAPE）調節TLR3，TLR4和RIG-I樣受體對I型乾擾素產生的途徑，在感染IAV的小鼠中提供保護性免疫能力。因此，在我的論文中對進一步闡了TAPE在預防IAV感染中的功能作用感興趣。 ELISA的結果顯示，在IAV感染，與WT cDC相比，TAPE缺陷的cDC在I型IFN產生中受損。該結果表明TAPE對於觸發原代cDC中針對IAV感染的I型IFN產生是至關重要的。

Influenza A virus (IAV) is the main pathogen causing respiratory diseases in humans and other species. It is known that several RNA sensors, including cytosolic RIG-I, endosomal Toll-like receptor 3 (TLR3) and TLR7, are involved in detecting IAV RNA to trigger type I interferon (IFN)-mediated antiviral immunity. Meantime, IAV employs the multiple strategies to evade antiviral defenses for its successful replication in host cells. Notably, the IAV nonstructural protein 1 (NS1) is shown to interfere RIG-I sensing via competing with RIG-I for binding viral RNA. It is of interest to further explore if IAV NS1 may employ other evasion mechanisms to impair antiviral responses. Previous studies from our group revealed a novel NS1-mediated immune evasion mechanism by which NS1 targeted an E3 ubiquitin ligase TRAF3 via a TRAF3-binding motif (TIM) in the C-terminal effector domain, resulting in the blockade of RIG-I signaling to type IFN induction. In addition to RIG-I, TRAF3 is also shown to link TLR3 and TLR7 signaling to type I IFN induction. Given these facts, my thesis work focuses on the following aims: (1) to study the functional role of IAV NS1 in counteracting RIG-I signaling in conventional dendritic cells (cDCs), (2) to study if NS1 may interfere with other RNA sensing pathways like TLR3 and TLR7, and (3) to further study the in vivo role of IAV NS1 TIM mutant virus during IAV infection. Our ex vivo studies indicated that during infection, IAV NS1 mutant virus carrying TIM mutation compared to IAV WT virus induced higher IFN-β production from cDCs. In addition, IAV NS1 TIM mutant showed the less blocking effect on the TLR3 and TLR7 pathways to type I IFN induction. In vivo results showed that mice infected with IAV NS1 TIM mutant virus compared to IAV WT virus led to a better survival rate. Further, infection of mice with IAV NS1 TIM mutant virus induced higher type I IFN production in the mouse lung at the early stage. Of interest, our vaccination experiments showed that the challenge of mice with IAV NS1 TIM mutant virus conferred protection against a lethal dose of WT virus infection. In summary, our data indicate that IAV NS1 counteracts multiple RNA sensing pathways through targeting TRAF3 in an RNA binding-independent manner, leading to the evasion of type I IFN-mediated antiviral defenses. Previous work from our lab has shown that TBK1-associated protein in endolysosomes (TAPE) is an innate immune regulator linking the TLR3, TLR4, and RIG-I like receptors pathways to type I IFN production and plays a key role in trigger protective immunity against IAV infection in vivo. Thus, my thesis work further assesses the functional role of TAPE in cDCs in response to IAV infection. Results from ELISA showed that TAPE deficiency impaired type-I IFN production from primary dendritic cells upon IAV infection. This result suggests that TAPE is critical for cDCs to trigger type I IFN production in response to IAV infection.

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