Vibrio cholerae infection of Drosophila melanogaster mimics the human disease cholera.
Vibrio cholerae infection of Drosophila melanogaster mimics the human disease cholera.
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果蝇的弧菌霍拉氏菌感染模仿人类疾病霍乱。
DOI：
10.1371/journal.ppat.0010008
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发表时间：
2005-09
期刊：
影响因子：
6.7
通讯作者：
Watnick, Paula I
中科院分区：
文献类型：
--
作者：
Blow, Nathan S;Salomon, Robert N;Garrity, Kerry;Reveillaud, Isabelle;Kopin, Alan;Jackson, F Rob;Watnick, Paula I
霍乱是由革兰氏阴性菌霍乱弧菌引起的大流行性腹泻病，仍然是发展中国家面临的重大公共卫生挑战。霍乱毒素是造成霍乱大量粪便的原因，它会引起腺苷酸环化酶的组成性激活，导致离子输出到肠腔中。环境研究表明霍乱弧菌与包括昆虫在内的许多节肢动物物种之间存在密切关系。在这里，我们报告了果蝇（Drosophila melanogaster）对口腔霍乱弧菌感染的易感性，其过程表现出人类疾病的许多特征：（i）果蝇的死亡取决于霍乱毒素的存在，并且随后体重迅速减轻； (ii) 携带腺苷酸环化酶 Gsα 或 Gardos K+ 通道同系物 SK 突变等位基因的果蝇对霍乱弧菌感染有抵抗力； (iii) 与霍乱弧菌一起摄入 K+ 通道阻断剂可保护野生型果蝇免于死亡。在哺乳动物中，摄入少至 25 微克的霍乱毒素就会导致严重腹泻。相比之下，我们发现摄入霍乱毒素对苍蝇来说并不致命。然而，当霍乱毒素与携带霍乱毒素编码基因染色体缺失的霍乱弧菌致病菌株共同施用时，果蝇随之死亡。这些发现表明，蝇类中毒需要额外的毒力因子，而哺乳动物中毒可能并非必需的。此外，我们首次证明了霍乱毒素在整个生物体中的作用机制，以及黑腹果蝇作为准确、廉价的模型来阐明宿主对霍乱的易感性的效用。霍乱是由革兰氏阴性菌霍乱弧菌引起的大流行性腹泻病，仍然是发展中国家面临的重大公共卫生挑战。环境研究表明，霍乱弧菌与许多节肢动物物种之间存在密切关系，而昆虫此前也被认为是这种疾病的传播媒介。在这里，研究人员报告了果蝇（Drosophila melanogaster）对口腔霍乱弧菌感染的易感性，其过程表现出许多人类疾病的特征。此外，虽然摄入霍乱毒素会导致哺乳动物严重腹泻，但这些研究人员发现，摄入纯化的霍乱毒素对于苍蝇来说并不致命。然而，当与携带霍乱毒素基因缺失的霍乱弧菌致病菌株共同摄入时，霍乱毒素是致命的。这些发现不仅证明了黑腹果蝇作为一种准确、廉价的模型，可用于阐明宿主-病原体相互作用和鉴定霍乱毒素作用的抑制剂；他们还表明，霍乱弧菌携带额外的毒力因子，使节肢动物宿主中毒。基于这些发现，研究人员认为苍蝇或相关节肢动物可能是自然界霍乱弧菌的真正宿主。
Cholera, the pandemic diarrheal disease caused by the gram-negative bacterium Vibrio cholerae, continues to be a major public health challenge in the developing world. Cholera toxin, which is responsible for the voluminous stools of cholera, causes constitutive activation of adenylyl cyclase, resulting in the export of ions into the intestinal lumen. Environmental studies have demonstrated a close association between V. cholerae and many species of arthropods including insects. Here we report the susceptibility of the fruit fly, Drosophila melanogaster, to oral V. cholerae infection through a process that exhibits many of the hallmarks of human disease: (i) death of the fly is dependent on the presence of cholera toxin and is preceded by rapid weight loss; (ii) flies harboring mutant alleles of either adenylyl cyclase, Gsα, or the Gardos K+ channel homolog SK are resistant to V. cholerae infection; and (iii) ingestion of a K+ channel blocker along with V. cholerae protects wild-type flies against death. In mammals, ingestion of as little as 25 μg of cholera toxin results in massive diarrhea. In contrast, we found that ingestion of cholera toxin was not lethal to the fly. However, when cholera toxin was co-administered with a pathogenic strain of V. cholerae carrying a chromosomal deletion of the genes encoding cholera toxin, death of the fly ensued. These findings suggest that additional virulence factors are required for intoxication of the fly that may not be essential for intoxication of mammals. Furthermore, we demonstrate for the first time the mechanism of action of cholera toxin in a whole organism and the utility of D. melanogaster as an accurate, inexpensive model for elucidation of host susceptibility to cholera. Cholera, the pandemic diarrheal disease caused by the gram-negative bacterium Vibrio cholerae, continues to be a major public health challenge in the developing world. Environmental studies have demonstrated a close association between V. cholerae and many species of arthropods, and insects have previously been implicated as vectors of this disease. Here researchers report the susceptibility of the fruit fly, Drosophila melanogaster, to oral V. cholerae infection through a process that exhibits many of the hallmarks of human disease. Furthermore, although ingestion of cholera toxin results in massive diarrhea in mammals, these researchers have found that ingestion of purified cholera toxin is not lethal to the fly. However, when co-ingested with a pathogenic strain of V. cholerae carrying a deletion of the cholera toxin genes, cholera toxin is lethal. These findings not only demonstrate the utility of D. melanogaster as an accurate, inexpensive model for elucidation of the host-pathogen interaction and identification of inhibitors of the action of cholera toxin; they also suggest that V. cholerae carries additional virulence factors that enable intoxication of an arthropod host. Based on these findings, the researchers suggest that the fly or a related arthropod may be a true host of V. cholerae in nature.