Integrated transcriptomic analysis reveals immune signatures distinguishing persistent versus resolving outcomes in MRSA bacteremia

Front Immunol. 2024 May 23:15:1373553. doi: 10.3389/fimmu.2024.1373553. eCollection 2024.

Abstract

Introduction: Staphylococcus aureus bacteremia (SAB) is a life-threatening infection particularly involving methicillin-resistant S. aureus (MRSA). In contrast to resolving MRSA bacteremia (RB), persistent MRSA bacteremia (PB) blood cultures remain positive despite appropriate antibiotic treatment. Host immune responses distinguishing PB vs. RB outcomes are poorly understood. Here, integrated transcriptomic, IL-10 cytokine levels, and genomic analyses sought to identify signatures differentiating PB vs. RB outcomes.

Methods: Whole-blood transcriptomes of propensity-matched PB (n=28) versus RB (n=30) patients treated with vancomycin were compared in one independent training patient cohort. Gene expression (GE) modules were analyzed and prioritized relative to host IL-10 cytokine levels and DNA methyltransferase-3A (DNMT3A) genotype.

Results: Differential expression of T and B lymphocyte gene expression early in MRSA bacteremia discriminated RB from PB outcomes. Significant increases in effector T and B cell signaling pathways correlated with RB, lower IL-10 cytokine levels and DNMT3A heterozygous A/C genotype. Importantly, a second PB and RB patient cohort analyzed in a masked manner demonstrated high predictive accuracy of differential signatures.

Discussion: Collectively, the present findings indicate that human PB involves dysregulated immunity characterized by impaired T and B cell responses associated with excessive IL-10 expression in context of the DNMT3A A/A genotype. These findings reveal distinct immunologic programs in PB vs. RB outcomes, enable future studies to define mechanisms by which host and/or pathogen drive differential signatures and may accelerate prediction of PB outcomes. Such prognostic assessment of host risk could significantly enhance early anti-infective interventions to avert PB and improve patient outcomes.

Keywords: MRSA; Staphylococcus aureus; host immunity; persistence; proteomics; transcriptomics.

MeSH terms

  • Adult
  • Aged
  • Anti-Bacterial Agents / therapeutic use
  • Bacteremia* / diagnosis
  • Bacteremia* / genetics
  • Bacteremia* / immunology
  • Bacteremia* / microbiology
  • DNA Methyltransferase 3A
  • Female
  • Gene Expression Profiling*
  • Humans
  • Interleukin-10 / blood
  • Interleukin-10 / genetics
  • Male
  • Methicillin-Resistant Staphylococcus aureus*
  • Middle Aged
  • Staphylococcal Infections* / diagnosis
  • Staphylococcal Infections* / genetics
  • Staphylococcal Infections* / immunology
  • Staphylococcal Infections* / microbiology
  • Transcriptome*

Substances

  • Interleukin-10
  • DNA Methyltransferase 3A
  • DNMT3A protein, human
  • Anti-Bacterial Agents

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. The present studies were supported by in-part by the following NIH grants U19-AI72713-01, U01-AI124319, R01-AI068804, R33-AI111661, and U19AI172713 (to MRY) and U01-AI124319, U19AL128913, and U19AI172713 (to EFR).