项目来源

香港研究资助局基金(RGC)

项目主持人

Dr Kok, Kin Hang

项目受资助机构

The University of Hong Kong

立项年度

2017

立项时间

未公开

项目编号

17124317

项目级别

省级

研究期限

未知 / 未知

受资助金额

1196388.00港币

学科

Medicine,Dentistry&Health

学科代码

未公开

基金类别

General Research Fund

关键词

未公开

参与者

Prof Chen,Honglin

参与机构

未公开

项目标书摘要：在过去几十年中，甲型流感病毒感染引致数百万人死亡。虽然有效的疫苗可用於保护季节性流感，但甲型流感病毒通过抗原性转移和抗原漂移不断进行变化，籍此逃避我们的免疫系统所控制。因此通过深入理解病毒与宿主之间的相互作用从而研发新抗病毒药物或疫苗，才能加强控制甲型流感病毒感染。
        先天免疫反应是控制各种呼吸道病毒感染的第一道防线。例如甲型流感病毒，受感染细胞会贞测到病毒RNA,并诱导产生一型或三型干扰素。未感染或已感染的细胞会受干扰素刺激从而开启抗病毒状态和控制病毒感染。在这个研究项目中，我们将会全面探讨一个受干扰素所刺激的基因，名为IFIRM,以及IFIRM对甲型流感病毒感染的作用。除了研究IFIRM在抑制甲型流感病毒中的分子机制，我们会利用转基因小鼠模型，确定甲型流感病毒感染过程中IFIRM的生理作用。总而言之，这个研究将揭示一个病毒与宿主相互作用的新机制，从而为控制甲型流感病毒感染提供重要基本知识。

Application Abstract: Infection of influenza A virus causes severe illness and millions of deaths in the past decades.Although effective vaccines are available for the protection of seasonal flu each year,influenza A viruses constantly undergo genetic changes through antigenic shift and antigenic drift to escape from our adaptive immune responses.Therefore,in-depth understandings of the early virus-host interaction,as well as the development of broad-spectrum vaccines and antivirals will lay the groundwork for the control of influenza A virus infection.Innate immune response is the first line of defence controlling various kinds of respiratory viral infections.As illustrated in influenza A virus infection,host pattern recognition receptor RIG-I specifically recognizes the viral RNAs in the virus-infected cells and rapidly induces the production of type-I/III interferons,by which awake the antiviral status of not only infected cells but also neighboring uninfected cells.We recently identified PACT,a host double-stranded RNA binding protein,as a potent activator of RIG-I and further demonstrated that the recognition of viral RNAs by PACT and RIG-I is indispensable for the optimal induction of interferons.In addition,we showed that herpes simplex virus-1(HSV-1)and Middle East respiratory syndrome coronavirus(MERS-CoV)suppress this PACT/RIG-I mediated interferon production by the expression of viral interferon antagonists Us11 and 4a proteins respectively.Conclusively,subversion of host interferon signaling by viral interferon antagonists is one of the key countermeasures adopted by various viruses to warrant their effective infections.Interferon molecules per se do not exhibit antiviral activity but,through activating the interferon receptors and their downstream signaling cascades,effectively induce the expression of hundreds of interferon-stimulated genes(ISGs).Some well-characterized ISGs are the key antiviral effectors,as exemplified by RIG-I,PKR and IFITM proteins which restrict influenza A virus infection by further inducing interferon expression,stabilizing interferon transcripts and blocking virus-host membrane fusion respectively.Based on the fact that the primary site of influenza A virus infection in human are the airway epithelial cells and underlying fibroblasts,we conducted a preliminary transcriptomic study and identified 132 ISGs commonly expressed in interferon-treated human lung fibroblasts and normal bronchial epithelial cells.Among these ISGs,we revealed a novel ISG named interferon-inducible regulator of m6A-modified RNA(IFIRM),of which expression exhibited antiviral activity in influenza A virus-infected cells.In this proposal,we will fully characterize the functional role of IFIRM during influenza A virus infection and investigate the underlying IFIRM-mediated antiviral mechanism.Our preliminary experimental data demonstrated that 1)IFIRM is a bona fide ISG potently induced in interferon-treated human lung fibroblasts and normal bronchial epithelial cells,2)IFIRM associated with the readers of N6-methyladenosine(m6A)RNA(YTHDF proteins),3)IFIRM associated with m6A-containing viral mRNAs during influenza A virus infection,and 4)IFI38 inhibited viral protein expression and influenza A virus infection.We hypothesized that IFIRM,together with YTHDF proteins,modulates the translation and/or the stability of viral mRNAs during influenza A virus infection.In this project,we will firstly examine the functional role of IFIRM;secondly investigate the molecular mechanism of IFIRM in the inhibition of influenza A virus;and finally determine the physiological role of IFIRM during influenza A virus infection using the tetracycline-inducible transgenic mouse model.Taken together,our proposed study will reveal a novel mechanism of virus-host interaction and hence provide important insights into the control of influenza A virus infection.;