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<p><i>Staphylococcus aureus</i> is a major human pathogen responsible for severe infections. While traditionally described as extracellular, increasing evidence establishes <i>S. aureus</i> as a facultative intracellular pathogen. Intracellularity contributes to immune evasion, dissemination, and antibiotic failure. To identify bacterial factors critical for <i>S. aureus</i> invasion, intracellular replication, persistence, and host cytotoxicity, we screened a comprehensive collection of 1920 <i>S. aureus</i> mutants (Nebraska Transposon Mutant Library) in epithelial cells across five timepoints (0.5 to 48 hours post-infection). We identified 73 bacterial factors strongly modulating <i>S. aureus</i> intracellularity, including mutants displaying multiple phenotypes. Most of these factors have not been linked to intracellular lifestyle. Among these, we characterized the nicotinamidase PncA as a novel regulator of the <i>agr</i> system via redox state modulation, strongly impacting virulence. This study provides a systematic analysis of <i>S. aureus</i> factors critical for intracellular lifestyle, with implications for the development of antimicrobial strategies targeting this resilient bacterial population.</p>

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Systematic identification of bacterial factors driving Staphylococcus aureus intracellular lifestyle in non-professional phagocytes

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月10日

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  • Ines Rodrigues Lopes,
  • Laura Maria Alcantara,
  • Maria Lopez-Bravo,
  • Yi Liu,
  • Gerald Larrouy-Maumus,
  • Daniel Lopez,
  • Miguel Mano,
  • Ana Eulalio

摘要

Staphylococcus aureus is a major human pathogen responsible for severe infections. While traditionally described as extracellular, increasing evidence establishes S. aureus as a facultative intracellular pathogen. Intracellularity contributes to immune evasion, dissemination, and antibiotic failure. To identify bacterial factors critical for S. aureus invasion, intracellular replication, persistence, and host cytotoxicity, we screened a comprehensive collection of 1920 S. aureus mutants (Nebraska Transposon Mutant Library) in epithelial cells across five timepoints (0.5 to 48 hours post-infection). We identified 73 bacterial factors strongly modulating S. aureus intracellularity, including mutants displaying multiple phenotypes. Most of these factors have not been linked to intracellular lifestyle. Among these, we characterized the nicotinamidase PncA as a novel regulator of the agr system via redox state modulation, strongly impacting virulence. This study provides a systematic analysis of S. aureus factors critical for intracellular lifestyle, with implications for the development of antimicrobial strategies targeting this resilient bacterial population.