Massicotte Marie-Ange, Fiebig Aline A, Bogza Andrei, Coombes Brian K
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
PLoS Pathog. 2025 Sep 9;21(9):e1013132. doi: 10.1371/journal.ppat.1013132. eCollection 2025 Sep.
Macrophages are professional phagocytes that play a major role in engulfing and eliminating invading pathogens. Some intracellular pathogens, such as Salmonella enterica serovar Typhimurium, exploit macrophages as niches for their replication, which requires precise and dynamic modulation of bacterial gene expression in order to resist the hostile intracellular environment. Here, we present a comprehensive analysis of the global transcriptome of S. Typhimurium across four stages of infection of primary macrophages. Our results revealed a profound change in early-stage gene expression dominated by pathways linked to metabolic processes required for Salmonella adaptation to the proinflammatory conditions of the macrophage. We identified the phage shock protein (Psp) system to be highly expressed in intracellular S. Typhimurium, with sustained high expression over the course of infection. We determined that the Psp system is regulated by the virulence-associated two-component system SsrA-SsrB, which coordinates its expression with critical bacterial functions required for immune evasion and intracellular survival. Functional assays demonstrated that the Psp system mediates resistance to host antimicrobial peptides, including cathelicidin-related antimicrobial peptide (CRAMP), which we demonstrate supports bacterial persistence in host tissues and survival within macrophages. Our findings establish the Psp system as a new and critical adaptive mechanism for evading host immune defenses and highlight the utility of temporal transcriptomics in unraveling the genetic strategies employed by S. Typhimurium during macrophage infection.
巨噬细胞是专业的吞噬细胞，在吞噬和清除入侵病原体方面发挥着主要作用。一些细胞内病原体，如鼠伤寒沙门氏菌，利用巨噬细胞作为其复制的场所，这需要精确且动态地调节细菌基因表达，以抵抗细胞内的恶劣环境。在此，我们对鼠伤寒沙门氏菌在原代巨噬细胞感染的四个阶段的全局转录组进行了全面分析。我们的结果揭示了早期基因表达的深刻变化，其主要由与沙门氏菌适应巨噬细胞促炎条件所需的代谢过程相关的途径主导。我们发现噬菌体休克蛋白（Psp）系统在细胞内的鼠伤寒沙门氏菌中高度表达，并且在感染过程中持续高表达。我们确定Psp系统受与毒力相关的双组分系统SsrA - SsrB调控，该系统将其表达与免疫逃避和细胞内存活所需的关键细菌功能相协调。功能测定表明，Psp系统介导对宿主抗菌肽的抗性，包括cathelicidin相关抗菌肽（CRAMP），我们证明其支持细菌在宿主组织中的持续存在以及在巨噬细胞内的存活。我们的研究结果确立了Psp系统作为逃避宿主免疫防御的一种新的关键适应性机制，并突出了时间转录组学在揭示鼠伤寒沙门氏菌在巨噬细胞感染期间所采用的遗传策略方面的效用。
