DecipheringStaphylococcus aureus-host dynamics using dual activity-based protein profiling of ATP-interacting proteins

Author:

Ahator Stephen DelaORCID,Hegstad KristinORCID,Lentz Christian S.,Johannessen Mona

Abstract

AbstractThe 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 betweenStaphylococcus aureusand 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. InS. aureus, 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 ofS. aureusto 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 ofS. aureus-host cell interactions, shedding light on modulating host immune responses toS. aureus, which could involve developing immunomodulatory therapies.ImportanceThis study uses a chemoproteomics approach to target active ATP-interacting proteins and examines the dynamic proteomic interactions betweenS. aureusand human cell lines THP-1 and HaCaT. It uncovers the distinct responses of macrophages and keratinocytes during bacterial infection.S. aureusdemonstrated 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 byS. aureusto persist within host cells. This study offers significant insights into the human cell response toS. aureusinfection, 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 againstS. aureusinfections.Graphical Abstract

Publisher

Cold Spring Harbor Laboratory

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