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Host-Receptor Post-Translational Modifications Refine Staphylococcal Leukocidin Cytotoxicity
Angelino T Tromp1, Michiel Van Gent1,2, Joris P Jansen1
1Department of Medical Microbiology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
Toxins
|February 12, 2020
Summary
Staphylococcal leukocidins target human phagocytes via G-protein coupled receptors (GPCRs). This study identified post-translational modification pathways, specifically sulfation and sialylation, impacting leukocidin-GPCR interactions and host susceptibility.
Area of Science:
- Microbiology
- Immunology
- Biochemistry
Background:
- Staphylococcal leukocidins are pore-forming toxins that lyse human phagocytes.
- Leukocidin S-components utilize G-protein coupled receptors (GPCRs) for cell targeting.
- Conserved characteristics of leukocidin-GPCR interactions remain largely unexplored.
Purpose of the Study:
- To investigate host cellular pathways influencing susceptibility to Staphylococcus aureus leukocidin cytotoxicity.
- To identify host factors mediating leukocidin-GPCR interactions.
Main Methods:
- Genome-wide CRISPR/Cas9 library screen for toxin resistance in U937 cells engineered to express GPCRs.
- Ectopic expression of various GPCRs to sensitize cells to leukocidins.
- Validation experiments to assess the impact of identified pathways on leukocidin toxicity.
Main Results:
- The screen identified post-translational modification (PTM) pathways, including sulfation and sialylation, as critical for leukocidin receptor function.
- PTM moieties on GPCRs differentially affect leukocidin-induced cytotoxicity.
- These findings reveal a refined layer of host-pathogen interaction.
Conclusions:
- PTM pathways significantly modulate the interaction between staphylococcal leukocidins and their GPCRs.
- Leukocidin receptors and their PTMs represent potential targets for anti-staphylococcal therapeutics.
- Genetic variations in PTM pathways may explain differential human susceptibility to S. aureus infections.
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