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

流感是一个全球性威胁。目前在中国爆发的H7N9禽流感具有高死亡率和可人传人的特点。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，拥有一种名为IFITM3的基因的特定遗传变异的人患严重流感感染的可能性是没有这种基因的人的6倍（Zhang等人，Nature Communications 2013）。这种变异基因在北欧人群中非常罕见，但在中国人中很常见。我们发现，69%的中国严重大流行性流感患者只有这种变异形式的IFITM3。相比之下，中国健康人的这一比例为25%。IFITM3蛋白抑制流感病毒进入细胞；这种变体被认为无法做到这一点。我们项目的一个关键目标将是检查这是否为真，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，但在中国，即使25%的人口只有这种IFITM3变异，严重流感也很罕见。因此，我们认为可能存在补偿性遗传因素和/或具有IFITM3变异的人的强烈免疫反应保护他们中的大多数人免受严重流感的侵害。因此，在本研究中，我们将在具有IFITM3易感基因但未患严重流感的中国人群中寻找其他保护基因。我们还将检查他们对病毒的免疫反应，并将其与不携带该基因变体的中国和英国人对流感病毒的免疫反应进行比较。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，实际上可能是导致问题的原因。我们还将研究T细胞免疫反应，这对感染病毒是特异性的，通常对快速清除病毒很重要。我们的初步数据表明，这些T细胞反应在携带IFITM3基因变异的中国人中更为活跃，这可能有助于弥补他们对严重感染增加的遗传易感性。通过这种方式，我们将更好地了解中国人严重感染的风险，这是由于这种基因变异在人群中非常常见。中国人遗传易感性的增加可能有助于流感病毒在东南亚的传播。我们将在H7N9禽流感新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能够超越（在欧洲）IFITM3的常见变体所提供的保护，以及该基因的这种版本是否会导致轻度无症状感染，我们之前已经证明这种感染发生在季节性流感、大流行性流感和禽流感中。我们与北京友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。这项研究解决了流感病毒感染尚未解决的重要问题，采取了全球而非局部的观点，这显然是应对这一威胁所必需的。

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.