Infection Immunology, Institute of Medical Microbiology, Health Campus Immunology, Infectiology and Inflammation, Otto-von-Guericke University, Magdeburg, Germany.
Immune Regulation, Helmholtz Centre for Infection Research, Braunschweig, Germany.
Front Immunol. 2021 Sep 30;12:724855. doi: 10.3389/fimmu.2021.724855. eCollection 2021.
The adhesion and degranulation-promoting adaptor protein (ADAP) serves as a multifunctional scaffold and is involved in the formation of immune signaling complexes. To date, only limited data exist regarding the role of ADAP in pathogen-specific immunity during infection, and its contribution in phagocyte-mediated antibacterial immunity remains elusive. Here, we show that mice lacking ADAP (ADAPko) are highly susceptible to the infection with the intracellular pathogen () by showing enhanced immunopathology in infected tissues together with increased morbidity, mortality, and excessive infiltration of neutrophils and monocytes. Despite high phagocyte numbers in the spleen and liver, ADAPko mice only inefficiently controlled pathogen growth, hinting at a functional impairment of infection-primed phagocytes in the ADAP-deficient host. Flow cytometric analysis of hallmark pro-inflammatory mediators and unbiased whole genome transcriptional profiling of neutrophils and inflammatory monocytes uncovered broad molecular alterations in the inflammatory program in both phagocyte subsets following their activation in the ADAP-deficient host. Strikingly, phagocytosis assay revealed impaired phagocytic capacity of neutrophils derived from -infected ADAPko mice. Together, our data suggest that an alternative priming of phagocytes in ADAP-deficient mice during infection induces marked alterations in the inflammatory profile of neutrophils and inflammatory monocytes that contribute to enhanced immunopathology while limiting their capacity to eliminate the pathogen and to prevent the fatal outcome of the infection.
黏附作用和脱颗粒促进衔接蛋白（ADAP）作为一种多功能支架，参与免疫信号复合物的形成。迄今为止，关于 ADAP 在 感染期间的病原体特异性免疫中的作用，仅有有限的数据，其在吞噬细胞介导的抗细菌免疫中的贡献仍然难以捉摸。在这里，我们表明，缺乏 ADAP（ADAPko）的小鼠对细胞内病原体 的感染高度敏感，表现为感染组织中的免疫病理学增强，发病率、死亡率和中性粒细胞和单核细胞的过度浸润增加。尽管脾脏和肝脏中的吞噬细胞数量很高，但 ADAPko 小鼠仅能低效地控制病原体生长，暗示在 ADAP 缺陷宿主中，感染激活的吞噬细胞的功能受损。对标志性促炎介质的流式细胞术分析和对中性粒细胞和炎症性单核细胞的无偏全基因组转录谱分析揭示了在 ADAP 缺陷宿主中，这两个吞噬细胞亚群在激活后炎症程序的广泛分子改变。引人注目的是，吞噬细胞摄取测定显示源自感染的 ADAPko 小鼠的中性粒细胞的吞噬能力受损。总之，我们的数据表明，ADAP 缺陷小鼠在 感染期间对吞噬细胞的替代激活诱导了中性粒细胞和炎症性单核细胞的炎症特征的显著改变，从而增强了免疫病理学，同时限制了它们消除病原体和防止感染致命后果的能力。
