Genomic analysis of malaria resistance

疟疾是人类最顽固、最致命的敌人之一，也是全球每年约5亿人罹患致贫疾病的重要决定因素。这种疾病的最大负担落在了非洲儿童身上--每年有100多万人死于疟疾。这个项目取决于一个关键的观察结果。许多人在疟疾感染后存活下来，在反复接触后，产生了一定程度的免疫力。我们的挑战是回答这个问题。保护人们免于因疟疾死亡或患病的自然免疫反应是什么？这里有两个我们所说的免疫反应的例子：(1)人产生抗体，附着在寄生虫表面的X分子上；(2)当白细胞接触疟疾寄生虫时，它们释放出杀死寄生虫的化学物质Y。知道这个问题的答案将极大地帮助设计一种有效的疟疾疫苗。研究人员已经解决这个问题近一个世纪了--为什么它这么难回答？部分问题是，感染疟疾的人会产生大量的免疫反应，这些反应没有任何保护作用，有些甚至可能是有害的。在所有这些不同的免疫反应中寻找那些保护人们免于生病或死亡的免疫反应就像大海捞针一样。更复杂的是，对抗疟疾寄生虫的大部分免疫战斗发生在脾和身体其他难以接触的部位，而这些部位在活人身上很难研究。人类基因组研究的最新进展正在彻底改变我们解决这类复杂问题的方式。关键的观察结果是，大多数人类基因在个体之间表现出差异。通过研究这种自然遗传变异如何影响人类抵抗感染的能力，我们可以深入了解保护性免疫的分子机制。为什么这是一个如此强大的方法？首先，因为它不需要我们直接测量蛋白质，所以我们可能能够识别重要的机制，即使它们在活人身上是不可能测量的--例如，它们是否隐藏在脾中。其次，因为新技术允许我们在对大量基因的功能一无所知的情况下对它们进行筛选，从而有可能发现对预防疟疾至关重要的全新机制。

Malaria is one of humankind‘s most persistent and deadly foes, and is a significant determinant of global poverty - causing debilitating illness in approximately half a billion people each year. The greatest burden of the disease falls on African children - over a million die each year of malaria.This project hinges on a key observation. Many people survive malaria infection and, after repeated exposure, develop some level of immunity.Our challenge is to answer this question. What are the natural immune responses that protect people from dying or becoming ill due to malaria? Here are two examples of what we mean by an immune response: (1) the person makes antibodies that attach to molecule X on the surface of the parasite; (2) when white blood cells come into contact with a malaria parasite they release chemical Y that kills the parasite. Knowing the answer to this question would help enormously in designing an effective malaria vaccine.Researchers have been tackling this question for almost a century - why is it so difficult to answer? Part of the problem is that people who are infected with malaria make a vast range of immune responses that have no protective benefit and some that may even be harmful. Searching through all these different immune responses to find those that protect people from becoming ill or dying is like searching for a needle in a haystack. To complicate matters further, much of the immune battle against the malaria parasite happens in the spleen and other inaccessible parts of the body that are very difficult to study in living people.Recent advances in human genome research are revolutionising the way that we tackle complex problems of this sort. The key observation is that most human genes show variation between individuals. By investigating how this natural genetic variation affects the ability of people to resist infection, we can get deep insights into molecular mechanisms of protective immunity.Why is this such a powerful approach? Firstly, because it doesn‘t require us to measure proteins directly, so we may be able to identify important mechanisms even if they are impossible to measure in living humans - e.g., if they are hidden away in the spleen. Secondly, because new technologies allow us to screen a vast number of genes without knowing anything about their function, making it possible to discover entirely novel mechanisms that are critical for protection against malaria.