# Epigenomic Mechanisms & Contextual Immunity in Persistent MRSA Bacteremia

> **NIH NIH U19** · LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER · 2023 · $528,279

## Abstract

PROJECT SUMMARY/ABSTRACT
 Staphylococcus aureus (SA) is the most common etiologic agent of bacteremia and hematogenous sequelae.
In methicillin-resistant SA (MRSA) bacteremia, up to 35% of patients succumb even on gold-standard antibiotic therapy,
equating to nearly 20,000 deaths/year in the U.S. alone. In many cases of MRSA bacteremia, isolates are susceptible
to antibiotics in vitro but not cleared from the bloodstream even on appropriate therapy. Survival of MRSA in vivo despite
antibiotic susceptibility in vitro is termed antibiotic persistence. Persistent MRSA bacteremia (PB) is a life-threatening
emergency correlating with worsened outcomes and escalation of antibiotic use. This vicious cycle of persistence
driving antibiotic escalation driving antibiotic resistance is an NIH high–priority concern.
 A long-standing mystery is central to PB infections: the MRSA isolate is susceptible to antibiotics in laboratory
testing—but not in the human being. Importantly, persistence reflects a unique type of treatment-refractory infections
distinct from biofilm-mediated or classical antibiotic tolerance or resistance. Rather, persistent MRSA are elusive: they
adapt to host immune responses and antibiotic stresses in vivo and then revert quickly in vitro. Presently, there are few
therapeutic options for PB due to MRSA. Further, despite several meritorious attempts, vaccines targeting MRSA have
not achieved efficacy in clinical trials to date. Thus, there is a critical, unmet need to define the interactions of the human,
MRSA pathogen and antibiotic factors driving persistence outcomes.
 To address these challenges, we have designed independent Specific Aims that are highly synergistic with those
of other Projects & Cores to: 1) specify the genetic and epigenetic mechanisms by which MRSA adaptively persists in
vivo; 2) discern how persistent MRSA subvert immune memory; and 3) define protective vs. non-protective immune
contexts that differentiate MRSA persistence vs. resolving outcomes. We will apply state-of-the-art technologies to
comprehensively analyze dynamic host-pathogen relationships leading to PB outcomes in context of antibiotic, host sex
and time in vitro and in experimental models. In turn, these data will be analyzed using powerful bioinformatics and
computational methods to detect hidden patterns within large complex datasets. Beyond new mechanistic insights, our
innovative studies are designed to discover translatable interventions that overcome MRSA persistence. This knowledge
will accelerate new strategies to predict, prevent and treat PB infections to improve and save lives. Strategies successful
in addressing MRSA persistence may also be applied to infections caused by other high-priority MDR pathogens. Our
systems-based approach to achieving these goals is ideally aligned with priorities of the National Institutes of Health.

## Key facts

- **NIH application ID:** 10551708
- **Project number:** 1U19AI172713-01
- **Recipient organization:** LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
- **Principal Investigator:** Michael R Yeaman
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $528,279
- **Award type:** 1
- **Project period:** 2023-08-10 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10551708

## Citation

> US National Institutes of Health, RePORTER application 10551708, Epigenomic Mechanisms & Contextual Immunity in Persistent MRSA Bacteremia (1U19AI172713-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10551708. Licensed CC0.

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