The homeostasis of malaria-infected red blood cells

恶性疟原虫引起人类最严重的疟疾，全世界每年有200多万人死亡，其中大多数是儿童。这种寄生虫对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的所有方面的深刻理解具有重大意义和潜在的治疗意义。寄生虫的反复无性生殖周期发生在人体红细胞中。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个或更多的寄生虫，准备感染新的红细胞并继续循环。在这个周期中，红细胞发生了巨大的变化。红细胞变得非常渗漏，以允许寄生虫需要的营养物质进入，并排出寄生虫产生的废物。此外，寄生虫投入大量的能量消化宿主细胞的大部分血红蛋白。令人困惑的是，这些食物中只有一小部分被利用;超过80%的消化产物被当作废物丢弃。从这些观察中产生了两个主要的科学难题：被寄生虫如此渗漏的红细胞如何避免在寄生虫需要复制的48小时之前膨胀和破裂，以及为什么寄生虫摄取和消化的血红蛋白比需要的多得多。一个受感染红细胞的数学模型为这两个难题提供了统一的解释（“胶体渗透假说”）：聪明的寄生虫需要大量消化血红蛋白，以降低将水驱入细胞的压力（胶体渗透压力），从而使泄漏的细胞完整地生存，直到寄生虫的繁殖周期结束。虽然初步测试的假设证明是支持的，关键的模型预测仍有待检验。该项目的目的是使用一组最先进的分析方法来测试这些预测。希望对受感染红细胞生物学这一方面的更好理解，除了其内在的科学兴趣之外，可能有助于开发新的治疗策略。这些药物的目的是诱导受感染的红细胞过早被破坏，释放出无法侵入新细胞的未成熟疟原虫。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专长的研究人员。

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.