近日，美国哈佛大学医学院John J. Mekalanos研究组发现霍乱毒素（CTX）帮助病原体获取从宿主来源的营养物质。这一研究成果发表在2019年8月8日出版的国际学术期刊《自然》上。

研究人员发现CTX促进病原体生长并引发明显的霍乱弧菌转录组标记，这是肠道微环境中铁元素耗尽的一个标志。在感染期间，细菌需要获取生长的必需营养元素—铁。哺乳动物宿主中的大多数铁在血红素的卟啉结构内以螯合形式存在，并且使用血红素作为铁源的能力由霍乱弧菌遗传编码。研究人员发现，只有当CTX产生时，让霍乱弧菌通过血红素获取铁的基因以及vibriobactin才能为病原体提供生长优势。此外，研究人员发现CTX诱导的回肠末端毛细血管充血与管腔血红素的生物利用度增加有关。回肠中CTX诱导的疾病还导致肠道中长链脂肪酸和L-乳酸等代谢物的浓度增加，以及编码含有铁-硫簇基因的三羧酸（TCA）循环酶霍乱弧菌基因的上调。霍乱弧菌的遗传分析表明病原体生长依赖于感染期间血红素和长链脂肪酸的摄取，但仅限于能够在体内产生CTX的菌株。因此，研究人员认为CTX引起的疾病在肠道中产生铁元素耗竭的代谢微环境，这种环境选择性地促进了通过获取宿主来源的血红素和脂肪酸的霍乱弧菌生长。

据悉，霍乱是一种可能致命的肠道细菌感染，霍乱弧菌是其致病因子。CTX是一种由霍乱弧菌分泌的蛋白质复合物，是霍乱弧菌引起严重疾病所必需的。CTX也被认为可以促进生物间的传播，因为受感染的个体会排出多升腹泻液，通常每升含有超过10的11次方个细菌。感染期间病原体如何在肠道中达到如此高的浓度仍然知之甚少。

附：英文原文

Title: Cholera toxin promotes pathogen acquisition of host-derived nutrients

Author: Fabian Rivera-Chvez, John J. Mekalanos

Issue&Volume: Volume 572 Issue 7768

Abstract: Vibrio cholerae is the causative agent of cholera, a potentially lethal enteric bacterial infection. Cholera toxin (CTX), a protein complex that is secreted by V. cholerae, is required for V. cholerae to cause severe disease. CTX is also thought to promote transmission of the organism, as infected individuals shed many litres of diarrhoeal fluid that typically contains in excess of 1011 organisms per litre. How the pathogen is able to reach such high concentrations in the intestine during infection remains poorly understood. Here we show that CTX increases pathogen growth and induces a distinct V. cholerae transcriptomic signature that is indicative of an iron-depleted gut niche. During infection, bacterial pathogens need to acquire iron, which is an essential nutrient for growth. Most iron in the mammalian host is found in a chelated form within the porphyrin structure of haem, and the ability to use haem as a source of iron is genetically encoded by V. cholerae. We show that the genes that enable V. cholerae to obtain iron via haem and vibriobactin confer a growth advantage to the pathogen only when CTX is produced. Furthermore, we found that CTX-induced congestion of capillaries in the terminal ileum correlated with an increased bioavailability of luminal haem. CTX-induced disease in the ileum also led to increased concentrations of long-chain fatty acids and l-lactate metabolites in the lumen, as well as the upregulation of V. cholerae genes that encode enzymes of the tricarboxylic acid (TCA) cycle that contain iron–sulfur clusters. Genetic analysis of V. cholerae suggested that pathogen growth was dependent on the uptake of haem and long-chain fatty acids during infection, but only in a strain capable of producing CTX in vivo. We conclude that CTX-induced disease creates an iron-depleted metabolic niche in the gut, which selectively promotes the growth of V. cholerae through the acquisition of host-derived haem and fatty acids.

DOI: 10.1038/s41586-019-1453-3

Source: https://www.nature.com/articles/s41586-019-1453-3