Leptospira interrogans stably infects zebrafish embryos, altering phagocyte behavior and homing to specific tissues.
Leptospira interrogans stably infects zebrafish embryos, altering phagocyte behavior and homing to specific tissues.
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DOI：
10.1371/journal.pntd.0000463
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发表时间：
2009-06-23
影响因子：
3.8
通讯作者：
Ramakrishnan L
中科院分区：
文献类型：
--
作者：
Davis JM;Haake DA;Ramakrishnan L
钩端螺旋体病是一种极为广泛的人畜共患传染病，其结果从亚临床感染到致命的韦氏综合征不等。尽管该疾病具有全球性影响，但其发病机制的关键方面仍不清楚。为了详细研究宿主对钩端螺旋体反应的最早步骤，我们使用荧光标记的钩端螺旋体血清型Copenhageni感染受精后30小时的斑马鱼胚胎的尾静脉或后脑脑室。这些胚胎具有先天免疫功能，但尚未发育出适应性免疫系统。此外，它们是光学透明的，允许从感染的那一刻起直接观察宿主-病原体相互作用。我们观察到钩端螺旋体被吞噬细胞快速摄取，随后在最初48小时内持续细胞内感染。钩端螺旋体的吞噬作用偶尔导致形成与凋亡小体一致的大细胞囊泡。到24小时时，感染的吞噬细胞簇聚集在背动脉外侧，推测是在早期造血组织中。我们的观察结果表明，吞噬作用可能是一个关键的防御机制，在钩端螺旋体病的早期阶段，吞噬细胞在免疫发病机制中发挥作用，并可能在传播的钩端螺旋体到特定的靶组织。钩端螺旋体病是一种常见的细菌感染，在世界上许多热带地区，导致严重的，往往是致命的疾病，在人类。这种感染是由携带者动物传播的，特别是老鼠和其他啮齿动物，它们将钩端螺旋体细菌从肾脏释放到尿液中。人类通过破损的皮肤或粘膜接触受污染的水而受到感染。关于细菌如何或为什么从这些部位专门到肾脏的交通知之甚少。斑马鱼胚胎是研究胚胎发育的流行模式生物，部分原因是透明胚胎内的活细胞可以在显微镜下轻松研究。在这项研究中，我们使用钩端螺旋体感染的斑马鱼胚胎检查早期钩端螺旋体病的显微镜。在感染的第一天，胚胎看起来正常。我们发现钩端螺旋体很容易被称为吞噬细胞的白色血细胞摄入（但不被杀死）。随后，在背主动脉附近的组织中发现了被感染的细胞。该部位可以是产生新血细胞的组织，并且可以代表用于生物体的后续组织靶向的导管。我们的研究结果表明，斑马鱼模型可能是有用的研究钩端螺旋体病的发病机制。
Leptospirosis is an extremely widespread zoonotic infection with outcomes ranging from subclinical infection to fatal Weil's syndrome. Despite the global impact of the disease, key aspects of its pathogenesis remain unclear. To examine in detail the earliest steps in the host response to leptospires, we used fluorescently labelled Leptospira interrogans serovar Copenhageni to infect 30 hour post fertilization zebrafish embryos by either the caudal vein or hindbrain ventricle. These embryos have functional innate immunity but have not yet developed an adaptive immune system. Furthermore, they are optically transparent, allowing direct visualization of host–pathogen interactions from the moment of infection. We observed rapid uptake of leptospires by phagocytes, followed by persistent, intracellular infection over the first 48 hours. Phagocytosis of leptospires occasionally resulted in formation of large cellular vesicles consistent with apoptotic bodies. By 24 hours, clusters of infected phagocytes were accumulating lateral to the dorsal artery, presumably in early hematopoietic tissue. Our observations suggest that phagocytosis may be a key defense mechanism in the early stages of leptospirosis, and that phagocytic cells play roles in immunopathogenesis and likely in the dissemination of leptospires to specific target tissues. Leptospirosis is a common bacterial infection in many tropical regions of the world that causes serious and often fatal disease in humans. The infection is transmitted by carrier animals, especially rats and other rodents, that release the leptospire bacteria from their kidneys into their urine. Humans are infected through exposure of broken skin or mucous membranes to contaminated water. Little is known about how or why the bacteria traffic from these sites specifically to the kidneys. The zebrafish embryo is a popular model organism for studying embryonic development, in part because of the ease with which living cells within the transparent embryos can be studied under the microscope. In this study, we use leptospire-infected zebrafish embryos to examine early leptospirosis by microscopy. In the first days of infection, the embryos appear normal. We find that leptospires are readily ingested (but not killed) by white blood cells called phagocytes. Later, infected cells are found specifically in a tissue near the dorsal aorta. This site may be a tissue that produces new blood cells and may represent a conduit for subsequent tissue targeting of the organisms. Our findings suggest that the zebrafish model may be useful for studying the pathogenesis of leptospirosis.
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