Department of Chemistry, Yale University, New Haven, CT, USA.
Institute of Biomolecular Design & Discovery, Yale University, West Haven, CT, USA.
Nat Commun. 2024 Oct 16;15(1):8902. doi: 10.1038/s41467-024-53185-6.
Virulent Klebsiella oxytoca strains are associated with gut and lung pathologies, yet our understanding of the molecular signals governing pathogenesis remains limited. Here, we characterized a family of K. oxytoca pyrazine and pyrazinone autoinducers and explored their roles in microbial and host signaling. We identified the human mucin capping sugar Neu5Ac as a selective elicitor of leupeptin, a protease inhibitor prevalent in clinical lung isolates of K. oxytoca, and leupeptin-derived pyrazinone biosynthesis. Additionally, we uncovered a separate pyrazine pathway, regulated by general carbohydrate metabolism, derived from a broadly conserved PLP-dependent enzyme. While both pyrazine and pyrazinone signaling induce iron acquisition responses, including enterobactin biosynthesis, pyrazinone signaling enhances yersiniabactin virulence factor production and selectively activates the proinflammatory human histamine receptor H4 (HRH4). Our findings suggest that the availability of specific carbohydrates delineates distinct autoinducer pathways in K. oxytoca that may have differential effects on bacterial virulence and host immune responses.
毒力型产酸克雷伯菌与肠道和肺部疾病有关，但我们对控制发病机制的分子信号的理解仍然有限。在这里，我们描述了一类产酸克雷伯菌吡嗪和吡嗪酮的自体诱导物，并探讨了它们在微生物和宿主信号转导中的作用。我们发现人类粘蛋白封端糖 Neu5Ac 是亮抑酶肽的选择性诱导物，亮抑酶肽是临床分离的产酸克雷伯菌中常见的一种蛋白酶抑制剂，而亮抑酶肽衍生的吡嗪酮生物合成。此外，我们还发现了一个由广泛保守的 PLP 依赖性酶调控的独立吡嗪途径。虽然吡嗪和吡嗪酮信号都能诱导铁摄取反应，包括enterobactin 生物合成，但吡嗪酮信号增强了耶尔森菌毒力因子的产生，并选择性地激活了促炎的人类组胺受体 H4（HRH4）。我们的研究结果表明，特定碳水化合物的可用性在产酸克雷伯菌中划定了不同的自体诱导物途径，这些途径可能对细菌毒力和宿主免疫反应产生不同的影响。
