Molecular turn in <i>Yersinia pestis</i> pathogenesis: implications of the <i>gppA</i> frameshift for bacterial survival in human macrophage

<i>Yersinia pestis</i>, the etiological agent of the devastating plague, has caused three pandemics in human history. While known for its fatality, it has long been intriguing that biovar microtus strains are highly attenuated to humans. The survival and replication within macrophages are critical in the early stages of the <i>Y. pestis</i> lifestyle within warm-blooded hosts. Here, we demonstrate that a frameshift truncation of <i>gppA</i>, a gene encoding the phosphohydrolase GppA that responsible for the conversion of stringent response alarmone pppGpp to ppGpp, significantly promotes <i>Y. pestis</i> to survive inside human macrophages. This frameshift mutation of <i>gppA</i> is present in all the evolutionary branches formed by the modern <i>Y. pestis</i> strains responsible for the plague pandemics, while the relative ancient microtus strains express a functional GppA showing high activity in catalyzing pppGpp to ppGpp conversion. This adaptive evolution potentially explains why microtus <i>Y. pestis</i> strains exhibit attenuated virulence in humans in contrast to the lethal pathogenicity of non-microtus strains. Transcriptome analysis suggests that the disturbed balance of the ratio of ppGpp to pppGpp caused by GppA inactivation results in an upregulation of genes involved in the synthesis of branched-chain amino acids, which are essential for bacterial growth. This enhanced survival ability within macrophages could be a key factor for the virulence of <i>Y. pestis</i> towards humans. Our work sheds light on the molecular mechanisms behind <i>Y. pestis</i> host-specific pathogenicity, offering significant implications for enhancing our ability to predict and counteract the emergence of new infectious diseases.鼠疫耶尔森菌（Yersinia pestis）作为毁灭性鼠疫的病原体，曾在人类历史上引发三次全球性大流行。尽管该菌以高致死性著称，但长期以来一个谜题始终困扰学界：microtus生物型菌株对人类的毒力极度减弱。在温血宿主的感染早期阶段，鼠疫耶尔森菌在巨噬细胞（macrophage）内的存活与增殖，是其生活史中的关键环节。本研究证实，编码磷酸水解酶GppA的gppA基因发生移码截短——该酶负责将严谨反应警报素pppGpp转化为ppGpp——可显著增强鼠疫耶尔森菌在人类巨噬细胞内的存活能力。该gppA基因的移码突变存在于所有引发鼠疫大流行的现代鼠疫耶尔森菌菌株所形成的进化分支中；而相对古老的microtus生物型菌株则表达具有功能的GppA，该酶可高效催化pppGpp向ppGpp的转化。这种适应性进化或可解释为何与非microtus生物型菌株的强致死性不同，microtus生物型鼠疫耶尔森菌菌株对人类的毒力显著减弱。转录组分析显示，GppA失活导致ppGpp与pppGpp的比例失衡，进而使参与支链氨基酸合成的基因表达上调，而支链氨基酸对细菌生长至关重要。这种在巨噬细胞内增强的存活能力，或许是鼠疫耶尔森菌对人类致病的关键因素。本研究揭示了鼠疫耶尔森菌宿主特异性致病的分子机制，为提升我们预测和应对新型传染病出现的能力提供了重要参考价值。

搜集汇总

背景与挑战

背景概述

该数据集聚焦于鼠疫耶尔森菌（Yersinia pestis）的致病分子机制，特别是gppA基因的移码突变如何增强细菌在人类巨噬细胞中的存活能力，从而解释不同菌株对人类毒力的差异。数据集包含实验数据（如Excel文件）和图像文件，支持转录组分析等研究，揭示了ppGpp与pppGpp比例失衡通过上调支链氨基酸合成基因影响细菌生长的机制。