The impact of IFTIM3 genetic variation on Influenza virus infection, immune responses and disease outcome

IFTIM3遗传变异对流感病毒感染、免疫反应和疾病结果的影响

• 批准号: MR/L018942/1
• 负责人: Tao Dong
• 金额: $ 112.91万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL018942%2F1
• 关键词: impact; IFTIM3; genetic; variation; Influenza

Influenza is a global threat. The current avian influenza H7N9 outbreak in China has a high death rate and can transmit from human-to-human. In this study, we will explore how human genetic factors and immune responses influence the severity of the disease. We recently found that people with a particular genetic variant of a gene called IFITM3 are six times more likely to suffer from severe influenza infection than those without (Zhang et al, Nature Communications 2013). This variant gene is very rare in Northern European populations but is common in Chinese people. We found that in 69% of Chinese patients with severe pandemic influenza had only this variant form of IFITM3. This compares to 25% of healthy Chinese individuals. The IFITM3 protein inhibits the entry of influenza virus into cells; the variant is thought to be unable to do this. One key aim of our project will be to check whether this is true and if so why it lacks this function. If more viruses enter cells the disease may be more severe, but severe influenza is rare in China even though 25% of the population have only this variant of IFITM3. Therefore we suggest that there may be compensating genetic factors snd/or that strong immune responses in people with the variant of IFITM3 protect most of them from severe influenza. In this study therefore, we will look for other protective genes in Chinese people who have the susceptible IFITM3 gene but who do not get severe influenza. We will also examine their immune responses to the virus and compare those with immune responses to influenza virus in Chinese and UK people who do not carry this gene variant. We will focus particularly on innate immune responses, which are known to be highly active in severe influenza and may actually contribute to the problem. We will also study T cell immune responses, which are specific for the infecting virus and are normally important for rapid viral clearance. Our preliminary data suggest that these T cell responses are more active in Chinese people with the IFITM3 gene variant, which could help compensate for their increased genetic susceptibility to severe infection.In this way we will gain a better picture of the risk of severe infection in Chinese people, conferred by this gene variant which is very common in the population. It is possible that increased genetic susceptibility in the Chinese helps the spread of influenza virus in South East Asia. We will examine this in the context of the new avian influenza H7N9 threat. We will ask whether this more aggressive virus can override the protection that the common (in Europeans) variant of IFITM3 offers and whether this version of the gene contributes to mild asymptomatic infection which we have previously shown to occur in seasonal, pandemic and avian influenza. Our special links to the infectious disease hospitals You'An and Ditan in Beijing make this unique study possible.This study addresses important unsolved problems of influenza virus infection, taking a global rather than local view, which is clearly necessary to tackle this threat.

流感是全球性的威胁。中国目前爆发的H7N9禽流感死亡率高，可在人与人之间传播。在这项研究中，我们将探讨人类遗传因素和免疫反应如何影响疾病的严重程度。我们最近发现，具有称为IFITM 3的基因的特定遗传变体的人患严重流感感染的可能性是没有的人的六倍（Zhang et al，Nature Communications 2013）。这种变异基因在北方欧洲人群中非常罕见，但在中国人中很常见。我们发现，在69%的严重大流行性流感患者中，只有IFITM 3的这种变异形式。这一比例在中国健康人群中为25%。IFITM 3蛋白抑制流感病毒进入细胞;该变体被认为无法做到这一点。我们的项目的一个关键目标是检查这是否是真的，如果是，为什么它缺乏这个功能。如果更多的病毒进入细胞，疾病可能会更严重，但严重的流感在中国是罕见的，尽管25%的人口只有IFITM 3的这种变体。因此，我们认为可能存在补偿性遗传因素，并且/或者IFITM 3变异体患者的强免疫应答保护了他们中的大多数人免受严重流感。因此，在本研究中，我们将在具有易感IFITM 3基因但未患严重流感的中国人中寻找其他保护性基因。我们还将检查他们对病毒的免疫反应，并比较不携带这种基因变异的中国人和英国人对流感病毒的免疫反应。我们将特别关注先天免疫反应，已知先天免疫反应在严重流感中高度活跃，实际上可能导致问题。我们还将研究T细胞免疫反应，这是特定的感染病毒，通常是重要的快速病毒清除。我们的初步数据表明，这些T细胞反应在IFITM 3基因变异的中国人中更活跃，这可能有助于弥补他们对严重感染的遗传易感性增加，这样我们就可以更好地了解中国人中严重感染的风险，这种基因变异在人群中非常常见。中国人的遗传易感性增加可能有助于流感病毒在东南亚的传播。我们将在新的H7N9禽流感威胁的背景下对此进行研究。我们将询问这种更具攻击性的病毒是否可以超越IFITM 3的常见（欧洲人）变体提供的保护，以及这种基因版本是否有助于我们以前在季节性流感，大流行性流感和禽流感中发生的轻度无症状感染。我们与北京佑安和地坛传染病医院的特殊联系使这项独特的研究成为可能。这项研究从全球而不是地方的角度解决了流感病毒感染的重要未解决问题，这显然是应对这一威胁所必需的。

项目成果

Malignant pleural effusion: Updates in diagnosis, management and current challenges.

• DOI: 10.3389/fonc.2022.1053574
• 发表时间: 2022
• 期刊: FRONTIERS IN ONCOLOGY
• 影响因子: 4.7
• 作者: Addala, Dinesh Narayan;Kanellakis, Nikolaos I.;Bedawi, Eihab O.;Dong, Tao;Rahman, Najib M.
• 通讯作者: Rahman, Najib M.