Many intracellular bacteria can establish chronic infection and persist in tissues within granulomas composed of macrophages. Granuloma macrophages exhibit heterogeneous polarization states, or phenotypes, that may be functionally distinct. Here, we elucidate a host-pathogen interaction that controls granuloma macrophage polarization and long-term pathogen persistence during Salmonella Typhimurium (STm) infection. We show that STm persists within splenic granulomas that are densely populated by CD11b+CD11c+Ly6C+ macrophages. STm preferentially persists in granuloma macrophages reprogrammed to an M2 state, in part through the activity of the effector SteE, which contributes to the establishment of persistent infection. We demonstrate that tumor necrosis factor (TNF) signaling limits M2 granuloma macrophage polarization, thereby restricting STm persistence. TNF neutralization shifts granuloma macrophages toward an M2 state and increases bacterial persistence, and these effects are partially dependent on SteE activity. Thus, manipulating granuloma macrophage polarization represents a strategy for intracellular bacteria to overcome host restriction during persistent infection.

中文翻译：

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沙门氏菌驱动的肉芽肿巨噬细胞极化在持续感染期间拮抗 TNF 介导的病原体限制。

许多细胞内细菌可以建立慢性感染并持续存在于由巨噬细胞组成的肉芽肿内的组织中。肉芽肿巨噬细胞表现出异质性极化状态或表型，这些状态可能在功能上是不同的。在这里，我们阐明了在鼠伤寒沙门氏菌 (STm) 感染期间控制肉芽肿巨噬细胞极化和长期病原体持久性的宿主-病原体相互作用。我们显示 STm 持续存在于由 CD11b+CD11c+Ly6C+ 巨噬细胞密集分布的脾脏肉芽肿中。STm 优先存在于重编程为 M2 状态的肉芽肿巨噬细胞中，部分是通过效应子 SteE 的活性，这有助于建立持续感染。我们证明肿瘤坏死因子 (TNF) 信号限制 M2 肉芽肿巨噬细胞极化，从而限制 STm 的持久性。TNF 中和将肉芽肿巨噬细胞转变为 M2 状态并增加细菌持久性，这些影响部分取决于 SteE 活性。因此，操纵肉芽肿巨噬细胞极化代表了细胞内细菌在持续感染期间克服宿主限制的一种策略。