Yersiniabactin contributes to overcoming zinc restriction during Yersinia pestis infection of mammalian and insect hosts
Yersiniabactin contributes to overcoming zinc restriction during Yersinia pestis infection of mammalian and insect hosts
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DOI：
10.1073/pnas.2104073118
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发表时间：
2021-10
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影响因子：
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通讯作者：
Sarah L. Price;V. Vadyvaloo;J. Demarco;A. Brady;Phoenix A. Gray;T. Kehl-Fie;S. Garneau‐Tsodikova;R. Perry;M. Lawrenz
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作者：
Sarah L. Price;V. Vadyvaloo;J. Demarco;A. Brady;Phoenix A. Gray;T. Kehl-Fie;S. Garneau‐Tsodikova;R. Perry;M. Lawrenz
过渡金属是正常细胞功能所必需的，这使得它们对所有生命都至关重要。为了限制细菌感染，真核生物主动隔离这些过渡金属，这一概念被称为营养免疫。因此，细菌病原体已经进化出专门的机制来获取过渡金属，以便在宿主中定殖。在人类鼠疫期间，鼠疫耶尔森氏菌通过分泌铁载体耶尔森氏菌素克服铁限制。在这里，我们确定了在哺乳动物感染和耶尔森氏菌感染中，耶尔森氏菌素在逃避锌介导的营养免疫中的非铁依赖性作用。跳蚤-昆虫载体的鼠疫定殖。重要的是，耶尔森氏菌素在几种病原体中发现，表明各种细菌利用它来获得多种金属，以克服营养免疫。鼠疫耶尔森氏菌引起人类鼠疫，并在其传播周期中在哺乳动物宿主和跳蚤载体上定居。细菌感染的关键屏障是宿主主动隔离关键生物金属的能力（例如，铁、锌和锰）。这被称为营养免疫。克服营养免疫的机制是细菌病原体的基本毒力因子。Y.鼠疫杆菌产生一种称为耶尔森氏杆菌素（Ybt）的铁清除铁载体，该铁载体是克服铁介导的营养免疫并引起致命感染所必需的。最近，Ybt已被证明与锌结合，在缺乏锌转运蛋白ZnuABC的情况下，Ybt改善了Y。鼠疫菌在限锌培养基中的生长。这些数据表明，除了铁的收购，Ybt也可能有助于克服锌介导的营养免疫。为了验证这一假设，我们使用了铁介导的营养免疫缺陷的小鼠模型来证明Ybt以不依赖铁的方式对毒力有贡献。此外，使用细菌突变体和锌介导的营养免疫缺陷小鼠的组合，我们确定钙卫蛋白是Y。鼠疫菌在感染过程中获得锌，而Y.鼠疫菌利用Ybt与钙卫蛋白竞争锌。最后，我们发现Y.鼠疫菌在跳蚤中肠内遇到锌限制，Ybt有助于克服这种限制。总之，这些结果表明Ybt是Y.鼠疫菌在感染哺乳动物和昆虫宿主期间克服锌限制。
Significance Transition metals are required for proper cellular function, which renders them critical for all life. To restrict bacterial infection, eukaryotic organisms actively sequester these transition metals, a concept referred to as nutritional immunity. Consequently, bacterial pathogens have evolved dedicated mechanisms to acquire transition metals in order to colonize the host. During human plague, Yersinia pestis overcomes iron limitation via the production of the secreted siderophore yersiniabactin. Here, we identify an iron-independent role for yersiniabactin in evading zinc-mediated nutritional immunity during mammalian infection and in Y. pestis colonization of the flea–insect vector. Importantly, yersiniabactin is found in several pathogens, indicating that a variety of bacteria use it to acquire multiple metals in order to overcome nutritional immunity. Yersinia pestis causes human plague and colonizes both a mammalian host and a flea vector during its transmission cycle. A key barrier to bacterial infection is the host’s ability to actively sequester key biometals (e.g., iron, zinc, and manganese) required for bacterial growth. This is referred to as nutritional immunity. Mechanisms to overcome nutritional immunity are essential virulence factors for bacterial pathogens. Y. pestis produces an iron-scavenging siderophore called yersiniabactin (Ybt) that is required to overcome iron-mediated nutritional immunity and cause lethal infection. Recently, Ybt has been shown to bind to zinc, and in the absence of the zinc transporter ZnuABC, Ybt improves Y. pestis growth in zinc-limited medium. These data suggest that, in addition to iron acquisition, Ybt may also contribute to overcoming zinc-mediated nutritional immunity. To test this hypothesis, we used a mouse model defective in iron-mediated nutritional immunity to demonstrate that Ybt contributes to virulence in an iron-independent manner. Furthermore, using a combination of bacterial mutants and mice defective in zinc-mediated nutritional immunity, we identified calprotectin as the primary barrier for Y. pestis to acquire zinc during infection and that Y. pestis uses Ybt to compete with calprotectin for zinc. Finally, we discovered that Y. pestis encounters zinc limitation within the flea midgut, and Ybt contributes to overcoming this limitation. Together, these results demonstrate that Ybt is a bona fide zinc acquisition mechanism used by Y. pestis to surmount zinc limitation during the infection of both the mammalian and insect hosts.