内容来源：https://www.quantamagazine.org/malaria-parasite-caught-in-the-act-of-breaking-and-entering-20261023/

内容总结：

科学家首次以空前细节捕捉到疟原虫侵入人体红细胞的关键瞬间，揭示了这一致命寄生虫“破门而入”的分子机制，为新一代抗疟药物研发提供了重要线索。相关研究由美国哥伦比亚大学微生物学家兼结构生物学家何志敏（Chi-Min Ho）实验室完成。

疟疾自古危害人类健康。20世纪，疟疾曾导致全球高达5%的死亡；如今每年仍造成约60万人死亡。1880年，法国医生拉韦朗通过简陋显微镜发现，疟疾的真正病原体并非“瘴气”，而是一种名为疟原虫的单细胞原生生物。此后，科学家逐步阐明了疟原虫的生命周期、宿主和致病过程，但其侵入宿主细胞的具体机制长期成谜。

疟原虫在侵入红细胞时，会在细胞膜上形成一个环状结构，称为“移动连接”。这一通道开启和关闭极快、尺度极小，传统成像技术难以捕捉。何志敏表示，正因如此，此前对其工作原理几乎一无所知。

在新研究中，何志敏团队利用冷冻电子显微镜，对移动连接在入侵瞬间的结构进行了高分辨率成像。研究发现，疟原虫向红细胞内注入三种蛋白质，在细胞膜下方形成致密楔形结构，另有第四种蛋白质将该结构与寄生虫本体相连。这些蛋白质在红细胞膜上产生静电力和压力，挤占并位移脂质分子，使细胞膜发生形变、曲率反转，最终在寄生虫进入后重新闭合，几乎不留痕迹。整个入侵过程不到一分钟。

未参与该研究的澳大利亚新南威尔士大学寄生虫学家杰克·鲍姆评价称，这是一项“令人脑洞大开的论文”，其本质更接近生物物理学而非传统分子生物学。

研究还揭示了疟原虫进入红细胞后如何“全面改造”宿主细胞。红细胞本身几乎没有细胞核和细胞器，疟原虫便从零开始构建自身生存所需的环境，分泌蛋白质摄取血红蛋白、清除废物并扩展细胞质。何志敏将其比作把空仓库改造成精装公寓，“它是在铺设管道、搭建楼层，几乎为自己建造一切”。

与此同时，疟原虫还会重塑红细胞外表面，表达一系列黏性蛋白，使感染细胞黏附在血管壁上，这也是疟疾疼痛症状的主要成因之一。2025年，纽约威尔康奈尔医学院柯克·戴奇实验室的研究发现，疟原虫通过周期性切换表面蛋白，可在数天至数周内逃避免疫系统识别。这种改造还能帮助寄生虫避免被脾脏过滤清除。

在红细胞内，疟原虫还会从圆形裂殖子转变为阿米巴样滋养体，伸出多个细胞质“手臂”并变得更为柔软，从而进一步规避免疫系统。随后，寄生虫在约48小时内进行无性繁殖，直至胀破红细胞，再侵入新的血细胞。数天内，数百万疟原虫便可能充斥血液。

研究人员认为，移动连接是阻断疟原虫感染的关键“卡点”。何志敏团队利用人工智能蛋白设计平台开发了一种抑制性蛋白，在试管实验中成功阻止疟原虫进入红细胞，但其安全性和有效性尚未在动物模型中验证。

移动连接还可能成为治疗其他寄生虫病的“万能钥匙”。疟原虫属于顶复门寄生虫，该门类还包括弓形虫和环孢子虫等，这些单细胞生物似乎使用相似的生化“入侵装备”。不过，也有学者指出，入侵过程过于短暂，任何阻断入侵的药物只有约60秒的作用窗口，因此作为药物靶点存在挑战。

何志敏团队已将目光投向下一目标，计划利用类似的冷冻电镜技术解析其他与疟疾感染相关的蛋白复合体结构。她说：“我们已经捕获了一头白鲸，接下来要去追寻其余的白鲸。”

编辑说明：本研究部分由西蒙斯基金会资助，该基金会同时资助本刊，但其资助决策不影响本刊报道。

中文翻译：

疟原虫在入侵的那一刻被逮个正着

引言

在中世纪的意大利，人们普遍认为，任何在沼泽附近行走的人都有可能因“坏空气”——mala aria——而染病。患者会发烧、头痛、恶心、发冷，偶尔病情会恶化到呕吐、黄疸甚至死亡。今天，我们仍然把这种疾病称为疟疾。在人类历史的大部分时间里，它肆虐于潮湿的热带和亚热带地区，夺去了无数人的生命。在20世纪，它造成的死亡占全球死亡人数的比例高达5%；时至今日，它每年仍夺去约60万人的生命。

直到大约150年前，疟疾究竟是什么、又是如何感染人类的，一直是个深深的谜团。1880年，法国医生夏尔·路易·阿方斯·拉韦朗透过一台简陋的显微镜观察一名士兵的血液样本，发现了这种疾病的真正病因：不是瘴气，而是一类形态多变、名为疟原虫的单细胞原生生物。自那以后，科学家和医生们精确地描述了这些寄生虫的生命周期、宿主和疾病进程，甚至不同疟原虫物种之间的细微差异——它们引发的疾病表现形式略有不同。但一些关键环节仍然是未解之谜。

例如，疟原虫在其生命周期中会入侵人类红细胞。为了进入细胞，这种微生物会构建一个名为“移动连接”的环状结构，在细胞膜上短暂地打开一个缺口，让自己滑入其中。随后，这个缺口便消失得无影无踪。它开合的速度如此之快、尺度如此之小，以至于成像技术根本无法捕捉。研究人员对这种门户结构的真实面貌一无所知。“正因如此，”哥伦比亚大学微生物学家和结构生物学家何芷敏说，“我们对它的运作机制几乎一无所知。”

如今，何芷敏的实验室在入侵发生的那一刻，以前所未有的细节对移动连接进行了成像。她的团队发现，当疟原虫在宿主细胞上安装分子密封圈时，它会彻底重塑细胞膜，从而不留痕迹地滑入其中。这一发现有望为下一代疟疾治疗提供思路，并影响其他寄生虫病（如环孢子虫病和弓形虫病）的药物研发进程。

“这是一篇令人脑洞大开的论文，”新南威尔士大学寄生虫学家杰克·鲍姆说，他并未参与这项研究。“说到底，这不是分子生物学，这是生物物理学。”

细胞改造工程

疟疾研究的历史与显微镜技术的进步并行发展，从拉韦朗使用的那种简易光学显微镜，到何芷敏实验室采用的尖端冷冻电镜技术。这是因为微生物入侵的细胞极其微小——而寄生虫本身更是小之又小。红细胞直径约8微米，是人体中最小的细胞之一，而在入侵阶段，所有种类的疟原虫都只有红细胞尺寸的零头大小。

对寄生虫入侵过程进行成像的尝试始于20世纪70年代，当时先驱微生物学家首次应用了电子显微镜。这些科学家观察到，在寄生虫进入点附近的细胞膜出现了明显的增厚。随后，这个微小的圆形疟原虫似乎只是与细胞融为一体，就像一滴水汇入更大的水池。又过了几十年，技术才发展到足以分离出实现这一过程的蛋白质，更不用说对它们进行成像了。

另一个障碍是，疟疾寄生虫的生命周期非常复杂。它们最舒适的家是蚊子的肠道，在那里它们可以进行有性繁殖。人类则是所谓的“储存宿主”——即寄生虫在等待被昆虫摄取期间栖身的地方。

“食物供应恰好就是我们的红细胞，”纽约威尔康奈尔医学院微生物学家和免疫学家柯克·戴奇说。“这就是它们入侵我们的原因。”

为此，疟原虫在经历各个生命阶段时会呈现出各种形状和大小：有时像鸡蛋，有时像细长的丝线，有时像瘦长的海星。它可以快速地走完这个周期，也可以在某个阶段（即人肝脏中的休眠子阶段）潜伏数年。当它进入微小的圆形裂殖子阶段时，寄生虫就准备好入侵红细胞了。

疟原虫带着它所需的全部蛋白质和其他生物装备抵达作案现场。入侵过程远比在宿主细胞上简单打个洞要精细得多。“如果你想把一个橙子塞进气球里，气球不能破，对吧？”鲍姆说。

根据此前的研究，科学家们已经了解了这一过程的总体轮廓。寄生虫接近宿主红细胞，向细胞膜中插入一圈蛋白质锚点。这些锚点统称为移动连接。疟原虫用其表面表达的蛋白质锁定这些锚点——然后向前推进。移动连接在宿主细胞膜上形成一个连续的通道，供寄生虫穿行。一旦寄生虫完全进入，细胞膜便在其身后封闭。整个过程不到一分钟。

何芷敏和这篇新论文的其他作者利用冷冻电镜探究了每个锚点中四个独立蛋白质单元的结构。他们所了解到的信息使他们能够提出一个更详细的模型，解释移动连接如何主动重塑宿主细胞膜。寄生虫向红细胞注入三种蛋白质，它们在膜表面下方形成一个致密的楔形结构；第四种蛋白质将这个结构连接到入侵者上。疟原虫在红细胞表面布置许多这样的锚点。这些蛋白质在细胞膜中产生静电力和压力，挤压并排开膜上的脂质分子。这使细胞膜变形并逆转其曲率。膜在寄生虫周围微微向内弯曲——事实上，一些脂质会脱落并重新组装成保护入侵者的膜——然后重新形成并在其身后封闭。

“这是一个非常好的例子，展示了一个领域如何一步一步地积累，最终达成一个真正有力的观察结果，”鲍姆说。

何芷敏供图

一旦进入细胞内部，疟原虫便会更全面地开展改造工作。红细胞本质上就是装满血红蛋白的袋子；它们没有细胞核，也谈不上有什么细胞器。因此，疟原虫要从零开始建设。它分泌蛋白质，使自己能够以血红蛋白为食、清除废物，并撑开细胞的细胞质。何芷敏将其比作把空旷的仓库改造成时尚的复式公寓。

“它在铺设管道，”她说。“它在铺地板。它简直是在为自己建造一切。”

在这个过程中，寄生虫还会重新装饰细胞的外部。它拥有能够制造一系列独特但密切相关的黏附蛋白的基因，并可以将这些蛋白表达在红细胞表面。这些蛋白质使细胞黏附在周围的血管壁上——这是疟疾疼痛症状的主要原因之一。2025年，戴奇实验室的研究发现，通过定期在这些蛋白质之间切换，寄生虫可以在数天或数周内避免引起免疫系统的注意。如此大规模的外部细胞改造有其目的：它帮助疟原虫避免前往脾脏——脾脏是一个过滤掉死亡、缺陷或破损红细胞以及任何潜伏寄生虫的器官。

美国国立卫生研究院国家过敏和传染病研究所，里克·费尔赫斯特和乔丹·祖斯潘

寄生虫本身在细胞内部也经历剧烈的变化。它从圆形的裂殖子转变为类似阿米巴的滋养体。它长出几条细胞质“手臂”并变平，英国基尔大学分子寄生虫学家克里斯蒂安·范·奥伊说。这也帮助它逃避免疫系统。滋养体的形状比球形的裂殖子更柔韧，而免疫系统会将柔软的细胞识别为健康细胞，将僵硬的细胞识别为死亡细胞。

随后，寄生虫进行约48小时的无性繁殖，在红细胞内不断分裂，直到细胞被疟原虫撑满而破裂。如同炒房客一样，寄生虫又转移到其他血细胞中。几天之内，数百万寄生虫就可能潜伏在血液中。

通过这种方式，疟疾可以迅速击垮人类宿主。这一切都依赖于移动连接，它让寄生虫能够安营扎寨而不引起“有关部门”的注意。移动连接的结构可以帮助研究人员进行干预，用药物从一开始就阻止寄生虫入侵宿主血细胞。

移动的靶标

疟疾治疗长期以来在某种程度上是一种碰运气的事。在没有深入了解疟原虫与宿主细胞相互作用的情况下，研究人员不得不通过反复试验来测试各种化合物。如果某种药物似乎能对抗疾病，他们也不太清楚它干扰了感染过程的哪个环节。“所有这些工作基本上都是盲目的，”戴奇说。

这使得开发新型疟疾治疗药物出了名的困难。曾经的主力抗疟药物，如氯喹、磺胺多辛和乙胺嘧啶，现在已知其靶标是血液中的寄生虫。但感染人类的疟原虫物种正在迅速进化出对这些化合物的耐药性。

入侵过程为新药提供了一个诱人的突破口。“如果你阻断了入侵，你就把寄生虫扼杀在半路上了，”何芷敏说。为了证明这一点，她的团队使用了一个AI驱动的蛋白质设计平台来构建一种抑制性蛋白质，可以阻断移动连接。在试管实验中，它阻止了疟原虫进入红细胞。但其安全性和有效性尚未在动物模型中进行测试。

移动连接有可能成为一把万能钥匙，用于治疗其他寄生虫病。疟原虫是顶复门的一员，这是一个庞大的寄生原生生物门类，还包括弓形虫（一种猫寄生虫）和环孢子虫（可引起爆发性腹泻）。这些单细胞生物似乎使用与疟原虫相同的生化装备进入宿主细胞。“所有这些寄生虫都拥有这套入侵机器，”戴奇说。对这些疾病的研究反过来也可以为疟疾治疗提供参考。2026年的一篇论文描述了弓形虫感知部署移动连接的正确时机的机制，而疟疾可能也以同样的方式运作。

但移动连接可能会被证明是一个太过善变的靶标。“有些人一直认为入侵是一个非常糟糕的药物靶点，因为这是一个非常短暂的过程，”范·奥伊说。任何能够阻止入侵的药物只有大约60秒的作用窗口，这意味着它需要在体内长时间保持稳定，或者起效极快，或者两者兼而有之。

何芷敏的团队已经把目光投向了另一个靶标。他们计划使用类似的冷冻电镜技术来解析疟疾感染中涉及的其他蛋白质复合物的结构，例如那些防止受感染血细胞前往脾脏的黏附蛋白。

“我们已经捕获了一头白鲸，”何芷敏说。“所以我们要去追寻其余的白鲸。”

编者按：本研究部分由西蒙斯基金会资助，该基金会也是本独立编辑杂志的资助方。西蒙斯基金会的资助决策对我们的报道内容没有任何影响。

英文来源：

Malaria Parasite Caught in the Act of Breaking and Entering
Introduction
In medieval Italy, it was accepted wisdom that anyone walking near a swamp risked falling ill from “bad air” — mala aria. Victims were struck with fever, headache, nausea, and chills, and occasionally the illness escalated to vomiting, jaundice, and death. Today, we still call this affliction malaria. For much of human history, it has ravaged populations in humid tropical and subtropical regions, killing untold numbers. In the 20th century, it was responsible for up to 5% of deaths worldwide; it still kills approximately 600,000 people each year.
What malaria was and how it infected humans was deeply mysterious until barely 150 years ago. In 1880, the French physician Charles Louis Alphonse Laveran peered at a sample of a soldier’s blood through a crude microscope and discovered the true cause of the disease: not miasma, but a genus of shape-shifting single-celled protists called Plasmodium. Since then, scientists and doctors have described in precise detail the parasites’ life cycle, hosts, and disease progression, and even the nuances of various Plasmodium species, which present slightly different forms of the disease. But some crucial aspects have remained a mystery.
For example, Plasmodium invades human red blood cells as part of its life cycle. To get in, the microbe creates a ring-shaped structure called the moving junction, which briefly creates a gap in the cell membrane it can slip through. The gap then disappears without a trace. It opens and closes so rapidly, at such a small scale, that imaging technologies couldn’t capture it. Researchers had no clue what the portal structure actually looked like. “Because of that,” said Chi-Min Ho, a microbiologist and structural biologist at Columbia University, “we didn’t really know anything about how it works.”
Now, Ho’s lab has imaged the moving junction right at the moment of invasion, in unprecedented detail. Her team found that when the Plasmodium parasite installs molecular gaskets in the host cell, it radically remodels the cell membrane to slip through without a trace. This knowledge could help inform the next generation of malaria treatments and influence the drug-discovery process for other parasitic diseases, such as cyclosporiasis and toxoplasmosis.
“It’s a totally mind-blowing paper,” said Jake Baum, a parasitologist at the University of New South Wales, who was not involved in the research. “At the end of the day, this is not molecular biology. This is biophysics.”
Home Remodeling
The history of malaria research has paralleled advances in microscopy, from the development of simple light microscopes like the one Laveran used to the cutting-edge cryo-electron techniques of Ho’s lab. This is because the cells the microbes invade are extremely tiny — and the parasites are even smaller. At about 8 micrometers across, red blood cells are among the smallest cells in the human body, and all species of Plasmodium are a fraction of that size during the invasion stage.
Attempts to image the parasites in the act of breaking and entering got off the ground in the 1970s, when pioneering microbiologists first applied electron microscopy. These scientists observed a distinct thickening of the cellular membrane near the parasite’s access point. Then the tiny, round Plasmodium seemed to simply merge with the cell, like a water droplet coalescing into a larger pool. It would be decades before techniques developed enough to isolate the proteins that make this possible, much less image them.
Another hurdle is that malaria parasites have a very complicated life cycle. They are most at home in the gut of a mosquito where they can reproduce sexually. Humans are what’s known as a reservoir host — a place for the parasite to live while it waits to be taken up by an insect.
“The food supply happens to be our red blood cells,” said Kirk Deitsch, a microbiologist and immunologist at Weill Cornell Medicine in New York. “That’s why they’re invading us.”
To this end, the Plasmodium parasite assumes a variety of shapes and sizes as it moves through its life stages: Sometimes it’s shaped like an egg, sometimes a spindly thread, sometimes a gangly starfish. It can move through this cycle in rapid succession or hang out in one stage (the hypnozoite phase in the human liver) for years. When it enters its tiny, round merozoite stage, the parasite is ready to invade a red blood cell.
Plasmodium pulls up to the scene of the crime with all the proteins and other biological equipment it needs. The entry procedure is more delicate than simply punching a hole in the host cell. “If you’re trying to push an orange into a balloon, the balloon mustn’t pop, right?” Baum said.
Based on previous research, scientists knew the broad strokes of this process. The parasite approaches a host red blood cell and inserts a ring of protein anchors into the cell’s membrane. Collectively these anchors are known as the moving junction. Plasmodium locks into them with proteins expressed on its surface — and then pushes forward. The moving junction forms a continuous portal in the host cell membrane for the parasite to travel through. Once the parasite is fully inside, the cell membrane seals up behind it. The whole process takes less than a minute.
Ho and the other authors of the new paper used cryo-electron microscopy to probe the four individual protein units in each anchor. What they learned allowed them to propose a more detailed model for how the moving junction actively remodels the host cell’s membrane. The parasite injects into the red blood cell three proteins, which form a dense wedge beneath the membrane surface; a fourth protein connects this structure to the invader. Plasmodium places many of these anchors on the red blood cell surface. The proteins produce electrostatic forces and pressure in the cell membrane, which crowd and displace its lipid molecules. This deforms the membrane and reverses its curvature. It bows slightly inward around the parasite — in fact, some lipids slough off and reassemble into a protective membrane for the invader — before re-forming and sealing behind it.
“It’s a really nice example of how a field has built step by step by step toward a really powerful observation,” Baum said.
Courtesy of Chi-Min Ho
Once inside, Plasmodium approaches its remodeling work more comprehensively. Red blood cells are essentially bags of hemoglobin; they have no nucleus or organelles to speak of. So Plasmodium builds from the ground up. It secretes proteins that allow it to feed on hemoglobin, remove waste, and stretch the cell’s cytoplasm. Ho compared it to the conversion of an empty warehouse floor into a stylish lofted apartment.
“It’s putting in plumbing,” she said. “It’s putting in the floors. It’s literally building everything for itself.”
In this process, the parasite also redecorates the cell’s exterior. It is equipped with genes that allow it to make a series of distinct but closely related adhesive proteins that it can express on the red blood cell’s surface. These proteins cause the cells to stick to the walls of the blood vessels around them — one of the main causes of malaria’s painful symptoms. In 2025, research from Deitsch’s lab found that by periodically switching between proteins, the parasite can avoid tipping off the immune system to its presence for days or weeks at a time. Such extensive exterior cellular remodeling serves a purpose: It helps Plasmodium avoid a trip to the spleen, an organ that filters out dead, defective, or broken red blood cells as well as any undercover parasites.
Rick Fairhurst and Jordan Zuspann, National Institute of Allergy and Infectious Diseases, National Institutes of Health
The parasite itself undergoes a radical change inside the cell. It transforms from a roundish merozoite into an amoebalike trophozoite. It grows several cytoplasm “arms” and flattens out, said Christiaan van Ooij, a molecular parasitologist at Keele University in the United Kingdom. This also helps it evade the immune system. The trophozoite shape is more flexible than that of the spherical merozoite, and the immune system clocks supple cells as healthy and stiff cells as dead.
The parasite then replicates asexually for about 48 hours, dividing inside the red blood cell until it’s so full of Plasmodium that it bursts. Like house flippers, the parasites move on to other blood cells. Within days, millions could be lurking in the bloodstream.
In this way, malaria can quickly overwhelm a human host. It is all enabled by the moving junction that allows the parasites to set up shop without tipping off the authorities. The structure of the moving junction could help researchers intervene, with drugs to block the parasite from invading a host blood cell in the first place.
Moving Target
Malaria treatment has long been something of a hit-or-miss proposition. Without a granular view of how Plasmodium interacts with host cells, researchers had to test various compounds by trial and error. If a given drug seemed to fight the illness, they had little idea what part of the infection process it had disrupted. “All that work was done essentially blind,” Deitsch said.
This has made developing new malaria treatments notoriously difficult. The former workhorse antimalarial drugs, such as chloroquine, sulfadoxine, and pyrimethamine, are now known to target the parasites in the bloodstream. But the Plasmodium species that infect humans are rapidly evolving resistance to these compounds.
Invasion offers a tantalizing choke point for new medicines. “If you block invasion, then you stop the parasite in its tracks,” Ho said. To make her point, her team used an AI-powered protein-design platform to craft an inhibitory protein that could block the moving junction. In test tubes, it prevented Plasmodium from entering red blood cells. But its safety and efficacy haven’t been tested in animal models.
It’s possible that the moving junction could be something of a skeleton key that could be used to treat other parasitic diseases. Plasmodium is a member of the apicomplexans, a large phylum of parasitic protists that also includes Toxoplasma gondii, a cat parasite, and Cyclospora, which causes explosive diarrhea. These single-celled organisms appear to enter using the same biochemical equipment as Plasmodium. “All of these are parasites that have this invasion machinery,” Deitsch said. The study of those conditions could in turn inform malaria treatment. A 2026 paper described the mechanism by which Toxoplasma senses the right moment to deploy its moving junction, and malaria may operate the same way.
But the moving junction may prove to be too much of a moving target. “Some people have always argued that invasion is a really bad drug target because it’s a very short process,” van Ooij said. Any drug with the ability to stop invasion would have a roughly 60-second window in which to do so, which means it would need to remain stable in the body for a long time or act extremely quickly, or both.
Ho’s team already has their sights set on another target. They plan to use similar cryo-electron microscopy techniques to solve the structure of other protein complexes involved in malaria infection, such as those adhesive proteins that keep infected blood cells from journeying to the spleen.
“We’ve caught one white whale,” Ho said. “So we want to go after the other remaining white whales.”
Editor’s note: This research was funded in part by the Simons Foundation, which also funds this editorially independent magazine. Simons Foundation funding decisions have no influence on our coverage.