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

流感是一个全球性的威胁。目前中国暴发的H7N9禽流感病死率高，可在人与人之间传播。在这项研究中，我们将探索人类遗传因素和免疫反应如何影响疾病的严重性。我们最近发现，携带一种名为IFITM3的特定基因变体的人患严重流感感染的可能性是不携带IFITM3基因的人的6倍(Zhang等人，《自然通讯》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，在69%的中国严重大流行性流感患者中，只有这种变异形式的IFITM3。相比之下，中国健康人群的这一比例为25%。IFITM3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。我们项目的一个关键目标将是检查这是否是真的，如果是的话，为什么它没有这个功能。如果更多的病毒进入细胞，疾病可能会更严重，但严重流感在中国患者中很少见，尽管25%的人口只有这种IFITM3变种。因此，我们认为可能存在代偿性遗传因素和/或携带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影响。因此，在这项研究中，我们将在中国人中寻找具有易感IFITM3基因但没有患上严重流感的其他保护性基因。我们还将检查他们对病毒的免疫反应，并比较中国人和英国人对流感病毒的免疫反应，这些人没有携带这种基因变体。我们将特别关注先天免疫反应，众所周知，先天免疫反应在严重流感中非常活跃，可能实际上导致了这个问题。我们还将研究T细胞免疫反应，这是感染病毒的特异性反应，通常对快速清除病毒很重要。我们的初步数据表明，在携带IFITM3基因变体的中国人中，这些T细胞反应更加活跃，这可能有助于弥补他们对严重感染的遗传易感性增加的影响。这样，我们将更好地了解这种基因变体在人群中非常常见的中国人严重感染的风险。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。我们将在新的禽流感H7N9威胁的背景下审查这一点。我们将询问这种更具攻击性的病毒是否可以超越常见的(在欧洲人中)IFITM3变种提供的保护，以及该基因版本是否有助于我们先前证明在季节性、大流行和禽流感中发生的轻度无症状感染。我们与北京右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。这项研究着眼于流感病毒感染的重要未解决问题，从全球而不是本地的角度来看，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.