Nuss Aaron M, Beckstette Michael, Pimenova Maria, Schmühl Carina, Opitz Wiebke, Pisano Fabio, Heroven Ann Kathrin, Dersch Petra
Department of Molecular Infection Biology, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany.
Department of Molecular Infection Biology, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany
Proc Natl Acad Sci U S A. 2017 Jan 31;114(5):E791-E800. doi: 10.1073/pnas.1613405114. Epub 2017 Jan 17.
Pathogenic bacteria need to rapidly adjust their virulence and fitness program to prevent eradication by the host. So far, underlying adaptation processes that drive pathogenesis have mostly been studied in vitro, neglecting the true complexity of host-induced stimuli acting on the invading pathogen. In this study, we developed an unbiased experimental approach that allows simultaneous monitoring of genome-wide infection-linked transcriptional alterations of the host and colonizing extracellular pathogens. Using this tool for Yersinia pseudotuberculosis-infected lymphatic tissues, we revealed numerous alterations of host transcripts associated with inflammatory and acute-phase responses, coagulative activities, and transition metal ion sequestration, highlighting that the immune response is dominated by infiltrating neutrophils and elicits a mixed T17/T1 response. In consequence, the pathogen's response is mainly directed to prevent phagocytic attacks. Yersinia up-regulates the gene and expression dose of the antiphagocytic type III secretion system (T3SS) and induces functions counteracting neutrophil-induced ion deprivation, radical stress, and nutritional restraints. Several conserved bacterial riboregulators were identified that impacted this response. The strongest influence on virulence was found for the loss of the carbon storage regulator (Csr) system, which is shown to be essential for the up-regulation of the T3SS on host cell contact. In summary, our established approach provides a powerful tool for the discovery of infection-specific stimuli, induced host and pathogen responses, and underlying regulatory processes.
致病细菌需要迅速调整其毒力和适应性程序，以防止被宿主根除。到目前为止，驱动发病机制的潜在适应过程大多是在体外进行研究的，而忽略了作用于入侵病原体的宿主诱导刺激的真正复杂性。在本研究中，我们开发了一种无偏倚的实验方法，可同时监测宿主和定殖于细胞外的病原体全基因组范围内与感染相关的转录变化。使用该工具对感染假结核耶尔森菌的淋巴组织进行研究，我们发现了许多与炎症和急性期反应、凝血活性以及过渡金属离子螯合相关的宿主转录本变化，突出表明免疫反应以浸润的中性粒细胞为主导，并引发混合的T17/T1反应。因此，病原体的反应主要是为了防止吞噬攻击。耶尔森菌上调抗吞噬III型分泌系统（T3SS）的基因和表达量，并诱导出对抗中性粒细胞诱导的离子剥夺、自由基应激和营养限制的功能。鉴定出了几种影响这种反应的保守细菌核糖调节因子。发现碳储存调节因子（Csr）系统的缺失对毒力影响最大，该系统被证明对于宿主细胞接触时T3SS的上调至关重要。总之，我们建立的方法为发现感染特异性刺激、诱导的宿主和病原体反应以及潜在的调节过程提供了一个强大的工具。
