Human macrophage polarization determines bacterial persistence of Staphylococcus aureus in a liver-on-chip-based infection model
Human macrophage polarization determines bacterial persistence of Staphylococcus aureus in a liver-on-chip-based infection model
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人类巨噬细胞极化决定了基于肝脏芯片的感染模型中金黄色葡萄球菌的细菌持久性
DOI：
10.1101/2021.11.19.469246
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通讯作者：
Mosig AS
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作者：
Siwczak F;Cseresnyes Z;Carlstedt S;Sigmund A;Gröger M;Surewaard BGJ;Werz O;Figge MT;Tuchscherr L;Löffler B;Mosig AS
金黄色葡萄球菌(S.aureus)感染的报告来自多个器官，从无症状的定植到严重的感染和与多器官功能障碍相关的败血症。虽然金黄色葡萄球菌被认为是一种细胞外病原体，但它可以入侵并持续存在于专业吞噬细胞，如单核细胞和巨噬细胞。它维持和操纵吞噬细胞的能力被认为是逃避宿主抗菌反应的关键一步。我们首次利用人类芯片上肝脏模型和定制的图像分析算法来证明金黄色葡萄球菌(USA300)特异性地针对肝脏模型中的巨噬细胞作为基本利基，促进细菌持久性和向小菌落变体(SCV)的表型转换。在体外，M2极化被发现有利于SCV的形成，并与巨噬细胞内细菌负荷增加、细胞死亡增加以及循环单核细胞向感染部位募集的损害有关。这些发现扩大了对肝巨噬细胞在全身感染过程中的作用的认识。此外，这一结果可能有助于理解慢性肝病患者的感染机制，例如纤维化，这些患者表现出M2极化的肝巨噬细胞频率增加，并有更高的慢性感染和复发性菌血症的风险。
Infections with Staphylococcus aureus (S. aureus) have been reported from various organs ranging from asymptomatic colonization to severe infections and sepsis associated with multiple organ dysfunction. Although considered an extracellular pathogen, S. aureus can invade and persist in professional phagocytes such as monocytes and macrophages. Its capability to persist and manipulate phagocytes is considered a critical step to evade host antimicrobial reactions. For the first time we leveraged a human liver-on-chip model and tailored image analysis algorithms to demonstrate that S. aureus (USA300) specifically targets macrophages in the liver models as essential niche facilitating bacterial persistence and phenotype switching to small colony variants (SCVs). In vitro M2 polarization was found to favor SCV-formation and was associated with increased intracellular bacterial loads in macrophages, increased cell death, and impaired recruitment of circulating monocytes to sites of infection. These findings expand the knowledge about the role of liver macrophages in the course of systemic infection. Further, the results might be relevant for understanding infection mechanisms in patients with chronic liver disease such as fibrosis that display increased frequencies of M2 polarized liver macrophages and have a higher risk for developing chronic infections and relapsing bacteremia.