Metabolic diversity of human macrophages: potential influence on Staphylococcus aureus intracellular survival

Blake P. Bertrand, Dhananjay Shinde, Vinai C. Thomas, Marvin Whiteley, Carolyn B. Ibberson, Tammy Kielian

Research output: Contribution to journalArticlepeer-review

Abstract

Staphylococcus aureus is a leading cause of medical device-associated biofilm infections. This is influenced by the ability of S. aureus biofilm to evade the host immune response, which is partially driven by the anti-inflammatory cytokine interleukin-10 (IL-10). Here, we show that treatment of human monocyte-derived macrophages (HMDMs) with IL-10 enhanced biofilm formation, suggesting that macrophage anti-inflammatory programming likely plays an important role during the transition from planktonic to biofilm growth. To identify S. aureus genes that were important for intracellular survival in HMDMs and how this was affected by IL-10, transposon sequencing was performed. The size of the S. aureus essential genome was similar between unstimulated HMDMs and the outgrowth control (18.5% vs 18.4%, respectively, with 54.4% overlap) but increased to 22.5% in IL-10-treated macrophages, suggesting that macrophage polarization status exerts differential pressure on S. aureus. Essential genes for S. aureus survival within IL-10-polarized HMDMs were dominated by negative regulatory pathways, including nitrogen and RNA metabolism, whereas S. aureus essential genes within untreated HMDMs were enriched in biosynthetic pathways such as purine and pyrimidine biosynthesis. To explore how IL-10 altered the macrophage intracellular metabolome, targeted metabolomics was performed on HMDMs from six individual donors. IL-10 treatment led to conserved alterations in distinct metabolites that were increased (dihydroxyacetone phosphate, glyceraldehyde-3-phosphate, and acetyl-CoA) or reduced (fructose-6-phosphate, aspartic acid, and ornithine) across donors, whereas other metabolites were variable. Collectively, these findings highlight an important aspect of population-level heterogeneity in human macrophage responsiveness that should be considered when translating results to a patient population.

Original languageEnglish (US)
JournalInfection and immunity
Volume92
Issue number2
DOIs
StatePublished - Feb 2024

Keywords

  • S. aureus
  • intracellular survival
  • macrophage
  • metabolism
  • transposon sequencing

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Infectious Diseases

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