The homeostasis of malaria-infected red blood cells

恶性疟原虫导致人类最严重的疟疾形式，全世界每年有200多万人死亡，其中大部分是儿童。这种寄生虫对可用于治疗疟疾的药物产生抗药性的速度与开发新的有效战略和治疗方法的速度之间存在着一场绝望的斗争。因此，对恶性疟原虫生物学各方面的深刻理解具有重大意义和潜在的治疗意义。寄生虫反复的无性繁殖周期发生在人的红细胞中。寄生虫侵入红细胞，发育和复制，大约48小时后细胞破裂，释放20或更多的寄生虫，准备感染新的红细胞并继续循环。在这个周期中，红细胞经历了戏剧性的变化。红细胞变得非常渗漏，以允许寄生虫所需的营养物质进入和寄生虫产生的废物离开。此外，寄生虫还会投入大量能量来摄取和消化宿主细胞的大部分血红蛋白。令人费解的是，这顿饭只有一小部分被使用；超过80%的消化产品被当作废物丢弃。这些观察产生了两个主要的科学难题：寄生虫造成的红细胞泄漏如何避免在寄生虫复制所需的48小时内提前肿胀和破裂，以及为什么寄生虫摄入和消化的血红蛋白比所需的要多得多。一个被感染的红细胞的数学模型为这两个谜题(胶体渗透假说)提供了统一的解释：聪明的寄生虫需要大量消化血红蛋白，以降低驱使水进入细胞的压力(胶体渗透压)，从而允许漏水的细胞完好无损地存活，直到寄生虫的繁殖周期结束。尽管对这一假说的初步测试证明是支持的，但关键的模型预测仍有待检验。这个项目的目的是使用一系列最先进的分析方法来测试这些预测。人们希望，除了内在的科学兴趣外，对受感染红细胞生物学这一方面的更好理解，可能有助于开发新的治疗策略。这些措施的目的是诱导受感染的红细胞过早破坏，释放无法入侵新细胞的未成熟疟疾寄生虫。该项目汇集了一组在细胞稳态数学建模、疟疾研究、X射线微量分析和先进光学成像方面具有高度互补性的专业知识的研究人员。

Plasmodium falciparum causes the most severe form of malaria in humans, with over two million deaths per year worldwide, mostly children. There is a desperate struggle between the rate at which this parasite develops resistance to the drugs available to treat malaria and the rate at which new effective strategies and treatments can be developed. A profound understanding of all the aspects of P. falciparum biology is therefore of major interest and potential therapeutic relevance. The recurrent asexual reproduction cycle of the parasite takes place in human red blood cells. A parasite invades a red cell, develops and replicates, and after about 48 hours the cell bursts releasing 20 or more parasites ready to infect new red cells and continue the cycle. During this cycle the red cell undergoes dramatic changes. The red cell becomes very leaky, to allow the entrance of nutrients the parasite needs and the exit of waste products the parasite generates. In addition, the parasite invests a lot of energy ingesting and digesting most of the haemoglobin of the hosting cell. Perplexingly, only a tiny fraction of this meal is used; over 80% of the digested products are discarded as waste. Two major scientific puzzles arise from these observations: how do red blood cells rendered so leaky by the parasite avoid swelling and bursting much earlier that the 48 hours the parasite needs to replicate, and why do the parasites ingest and digest so much more haemoglobin than needed. A mathematical model of an infected red cell provided a unifying explanation to both puzzles (the 'colloidosmotic hypothesis'): the clever parasite needs to digest haemoglobin in large excess to reduce the pressure that drives water into the cells (colloidosmotic pressure) thus allowing the leaky cell to survive intact until the end of the parasite's reproduction cycle. Although initial tests of the hypothesis proved supportive, critical model predictions remain to be tested. The purpose of this project is to test these predictions using a battery of state-of-the-art analytical methodologies. It is hoped that an improved understanding of this aspect of the biology of the infected red blood cell, besides its intrinsic scientific interest, may help develop new therapeutic strategies. These will be aimed at inducing the premature destruction of the infected red cells, with the release of immature malaria parasites unable to invade new cells. The project brings together a team of researchers with highly complementary expertise in mathematical modelling of cellular homeostasis, malaria research, X-ray microanalysis, and advanced optical imaging.