AUTHOR=Parmar Rajesh , Pickering Harry , Ahn Richard , Rossetti Maura , Gjertson David W. , Ruffin Felicia , Chan Liana C. , Fowler Vance G. , Yeaman Michael R. , Reed Elaine F. ,  MRSA Systems Immunology Group , Parmar Rajesh , Ahn Richard , Chan Liana C. , Bayer Arnold S. , Chang Yu-Ling , Filler Scott G. , Jr. Vance G. Fowler , Gjertson David , Hoffmann Alexander , Medie Felix Mba , Mikkaichi Tsuyoshi , Mitchell Simon , Qin Yan , Reed Elaine F. , Rossetti Maura , Ruffin Felicia , Sharma-Kuinkel Batu K. , Sheu Katherine , Thaden Joshua , Waring Alan J. , Xiong Yan Q. , Zheng Ying , Yeaman. Michael R. 

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

JOURNAL=Frontiers in Immunology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1373553

DOI=10.3389/fimmu.2024.1373553

ISSN=1664-3224

ABSTRACT=<sec><title>Introduction</title><p><italic>Staphylococcus aureus</italic> bacteremia (SAB) is a life-threatening infection particularly involving methicillin-resistant <italic>S. aureus</italic> (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.</p></sec><sec><title>Methods</title><p>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 (<italic>DNMT3A</italic>) genotype.</p></sec><sec><title>Results</title><p>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 <italic>DNMT3A</italic> heterozygous A/C genotype. Importantly, a second PB and RB patient cohort analyzed in a masked manner demonstrated high predictive accuracy of differential signatures.</p></sec><sec><title>Discussion</title><p>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 <italic>DNMT3A</italic> 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.</p></sec>