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

ABSTRACT:

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 1,920 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.

INSTRUMENT(S): Liquid Chromatography MS - positive

PROVIDER: MTBLS13220 | MetaboLights | 2025-10-26

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS13220_LC-MS_positive__metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS13220_LC-MS_positive__metabolite_profiling_v2_maf.tsv	Tabular
	s_MTBLS13220.txt	Txt

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Project description:Staphylococcus aureus is a human pathogen that can cause a wide range of diseases. Although formerly regarded as extracellular pathogen, it has been shown that S. aureus can also be internalized by host cells and persist within these cells. In the present study, we comparatively analyzed survival and physiological adaptation of S. aureus HG001 after internalization by two human lung epithelial cell lines (S9 and A549), and human embryonic kidney cells (HEK 293). Combining enrichment of bacteria from host-pathogen assays by cell sorting and quantitation of the pathogen's proteome by mass spectrometry we characterized S. aureus adaptation during the initial phase between 2.5 h and 6.5 h post-infection. Starting with about 2 × 10^6 bacteria, roughly 1450 S. aureus proteins, including virulence factors and metabolic enzymes were identified by spectral comparison and classical database searches. Most of the bacterial adaptation reactions, such as decreased levels of ribosomal proteins and metabolic enzymes or increased amounts of proteins involved in arginine and lysine biosynthesis, enzymes coding for terminal oxidases and stress responsive proteins or activation of the sigma factor SigB were observed after internalization into any of the three cell lines studied. However, differences were noted in central carbon metabolism including regulation of fermentation and threonine degradation. Since these differences coincided with different intracellular growth behavior, complementary profiling of the metabolome of the different non-infected host cell types was performed. This revealed similar levels of intracellular glucose but host cell specific differences in the amounts of amino acids such as glycine, threonine or glutamate. With this comparative study we provide an impression of the common and specific features of the adaptation of S. aureus HG001 to specific host cell environments as a starting point for follow-up studies with different strain isolates and regulatory mutants. Metabolome analysis, by nuclear magnetic resonance spectroscopy, was performed for the infection medium (extracellular medium, mock infection of 1 h).

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

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