Centre for New Antibacterial Strategies (CANS) & Research Group for Host-Microbe Interactions, Department of Medical Biology, Faculty of Health Sciences, UiT-The Arctic University of Norway, Tromsø, Norway.
Norwegian National Advisory Unit on Detection of Antimicrobial Resistance, Department of Microbiology and Infection Control, University Hospital of North Norway, Tromsø, Norway.
mSystems. 2024 May 16;9(5):e0017924. doi: 10.1128/msystems.00179-24. Epub 2024 Apr 24.
The utilization of ATP within cells plays a fundamental role in cellular processes that are essential for the regulation of host-pathogen dynamics and the subsequent immune response. This study focuses on ATP-binding proteins to dissect the complex interplay between and human cells, particularly macrophages (THP-1) and keratinocytes (HaCaT), during an intracellular infection. A snapshot of the various protein activity and function is provided using a desthiobiotin-ATP probe, which targets ATP-interacting proteins. In , we observe enrichment in pathways required for nutrient acquisition, biosynthesis and metabolism of amino acids, and energy metabolism when located inside human cells. Additionally, the direct profiling of the protein activity revealed specific adaptations of to the keratinocytes and macrophages. Mapping the differentially activated proteins to biochemical pathways in the human cells with intracellular bacteria revealed cell-type-specific adaptations to bacterial challenges where THP-1 cells prioritized immune defenses, autophagic cell death, and inflammation. In contrast, HaCaT cells emphasized barrier integrity and immune activation. We also observe bacterial modulation of host processes and metabolic shifts. These findings offer valuable insights into the dynamics of -host cell interactions, shedding light on modulating host immune responses to , which could involve developing immunomodulatory therapies.
This study uses a chemoproteomic approach to target active ATP-interacting proteins and examines the dynamic proteomic interactions between and human cell lines THP-1 and HaCaT. It uncovers the distinct responses of macrophages and keratinocytes during bacterial infection. demonstrated a tailored response to the intracellular environment of each cell type and adaptation during exposure to professional and non-professional phagocytes. It also highlights strategies employed by to persist within host cells. This study offers significant insights into the human cell response to infection, illuminating the complex proteomic shifts that underlie the defense mechanisms of macrophages and keratinocytes. Notably, the study underscores the nuanced interplay between the host's metabolic reprogramming and immune strategy, suggesting potential therapeutic targets for enhancing host defense and inhibiting bacterial survival. The findings enhance our understanding of host-pathogen interactions and can inform the development of targeted therapies against infections.
细胞内 ATP 的利用在细胞过程中起着基本作用，这些过程对于宿主-病原体动态的调节和随后的免疫反应至关重要。本研究聚焦于 ATP 结合蛋白，以剖析 与人类细胞（特别是巨噬细胞（THP-1）和角质形成细胞（HaCaT））在细胞内感染过程中的复杂相互作用。使用针对 ATP 相互作用蛋白的去硫生物素-ATP 探针提供了各种蛋白质活性和功能的快照。在 中，当位于人类细胞内时，我们观察到富含用于获取营养物质、氨基酸生物合成和代谢以及能量代谢的途径的富集。此外，直接对蛋白质活性进行的剖析揭示了 对角质形成细胞和巨噬细胞的特定适应。将差异激活的蛋白质映射到具有细胞内细菌的人类细胞中的生化途径，揭示了针对细菌挑战的细胞类型特异性适应，其中 THP-1 细胞优先进行免疫防御、自噬细胞死亡和炎症。相比之下，HaCaT 细胞强调了屏障完整性和免疫激活。我们还观察到细菌对宿主过程的调节和代谢转变。这些发现为 -宿主细胞相互作用的动态提供了有价值的见解，并揭示了调节宿主对 的免疫反应的机制，这可能涉及开发免疫调节疗法。
本研究使用化学蛋白质组学方法靶向活性 ATP 相互作用蛋白，并检查了 与人类细胞系 THP-1 和 HaCaT 之间动态蛋白质组相互作用。它揭示了巨噬细胞和角质形成细胞在细菌感染过程中的不同反应。 表现出对每种细胞类型的细胞内环境的针对性反应，并在暴露于专业和非专业吞噬细胞时进行适应。它还突出了 为在宿主细胞内生存而采用的策略。本研究为人类细胞对 感染的反应提供了重要的见解，阐明了巨噬细胞和角质形成细胞防御机制背后的复杂蛋白质组转变。值得注意的是，该研究强调了宿主代谢重编程和免疫策略之间的微妙相互作用，为增强宿主防御和抑制细菌存活提供了潜在的治疗靶点。研究结果增强了我们对宿主-病原体相互作用的理解，并为针对 感染的靶向治疗提供了信息。
