The Effect Of Malaria Parasites On Dendritic Cell Metabolism (TEMPODM)

疟疾流行地区的儿童对感染或儿童疫苗等免疫挑战的免疫反应减弱。这给疟疾疫苗带来了一个特别严重的问题，与非暴露于疟疾的(西方)人口相比，疟疾疫苗在暴露于疟疾的人群中效果要差得多。我们团队和其他人的研究导致了一种假设，即疟疾阻止了两个关键免疫细胞--T细胞和树突状细胞(DC)之间的物理相互作用。T细胞与DC的相互作用对于形成对感染或疫苗的保护性免疫反应至关重要。为了理解为什么会发生这种情况，我们发现，当疟疾寄生虫被DC吃掉时，它们会破坏细胞能量的关键生成器，称为线粒体。虽然这应该会导致DC死亡，但我们已经证明DC通过使用其他能源生成方法来适应生存。我们认为，这种能量的丧失或由此导致的适应过程，导致了疟疾感染期间DC功能的失效。癌症研究人员也对这些过程感兴趣，因为这是肿瘤细胞存活的重要途径，因此，有许多药物可以干预这些过程。因此，我们可以使用这些药物作为工具来了解哪些适应方面在DC功能丧失中起重要作用，以及这些方面是否允许T/DC相互作用进行。最后，我们假设，在疟疾流行地区，识别能够重建T细胞/DC相互作用的药物可以用于加强保护性疫苗接种。

Children in malaria endemic regions have weakened immune responses against immune challenges, such as infection or childhood vaccines. This poses a particularly significant problem for malaria vaccines, which have been much less successful in malaria exposed, compared with non-exposed (western) populations. Research by our team, and others, has led to the hypothesis that malaria blocks the physical interaction of two key immune cells, T cells and Dendritic Cells (DC). The interaction of T cells with DC is essential to form a protective immune response to infections or vaccines. To understand why this happens, we found that when malaria parasites are eaten by DC they damage the key generators of cellular energy, called mitochondria. While this should cause DC to die, we have shown that DC adapt by using other energy generating approaches to stay alive. We believe that this loss of power, or the adaptation process resulting from this, produces the failure in DC function during malaria infection. These processes are also of interest to cancer researchers, as an important way for tumour cells to stay alive, as a result, there are many drugs available to interfere with these processes. We can therefore use these drugs as tools to understand which aspects of adaptation are important in loss of DC function, and whether these allow T/DC interactions to proceed. Finally, we hypothesise that identifying drugs that can re-establish T cell/DC interactions in the face of malaria can be used enhance protective vaccination in malaria endemic regions.