Host immune and metabolic determinants of staphylococcus aureuspersister survival

The National Institute of Allergy and Infectious Diseases awarded the University of Nebraska $137,005 on August 1, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to investigate host immune and metabolic determinants of Staphylococcus aureus persister survival.

The research examines how S. aureus persister cells—dormant bacterial populations that survive antibiotic therapy—interact with the host immune system and evade antimicrobial responses. Aim 1 defines mechanisms by which persisters withstand antimicrobial agents within macrophages and neutrophils, focusing on resistance to reactive oxygen and nitrogen species. Aim 2 determines whether persisters manipulate host immunity to promote persistence through modulation of cytokine responses, immune cell recruitment, and macrophage function. The research addresses the central hypothesis that persister formation provides survival advantages during infection by tolerating innate immune antimicrobial components and dampening host immune responses, with implications for treating chronic staphylococcal infections including biofilm-associated device infections, osteomyelitis, cystic fibrosis, and endocarditis.

Performance occurs in Kearney, Nebraska, with a period of performance from August 1, 2026, through July 31, 2030. This is a project grant, the assistance type for investigator-initiated research under the program.

Abstract

Antibiotic therapy is thought to be unsuccessful against chronic bacterial infections for one of two reasons - resistance and tolerance. Countless studies have focused on resistance, and even though there are important implications to human health, the mechanism behind tolerance is poorly understood. Tolerance is mediated by persister cells, which are formed by all major pathogenic bacteria. Chronic staphylococcal infections including indwelling devices, osteomyelitis, cystic fibrosis, endocarditis, and other deep-seated infections are associated with biofilms. Many antibiotics are proficient at killing growing cells and we rely on the immune system to clear the remaining dormant persister population. Biofilms are especially problematic, as they protect persisters from the immune system. The mechanism of persister formation in gram-positive pathogens like staphylococcus aureus and staphylococcus epidermidis remained elusive until recently. Recent studies in s. Aureus link persister formation to reduced tricarboxylic acid (TCA) cycle activity, yet how these cells interact with the host immune system is largely unknown. Importantly, persistence is not only a barrier to antimicrobial therapy but may also allow bacteria to evade and reshape host immune responses, contributing to chronic, difficult-to-treat infections. This proposal tests the central hypothesis that s. Aureus persister formation provides a survival advantage during infection by tolerating innate immune antimicrobial components and dampening host immune responses. Aim 1 will define the mechanisms by which persisters withstand antimicrobial agents within macrophages, and neutrophils, with a focus on resistance to reactive oxygen and nitrogen species. Aim 2 will determine whether persisters manipulate host immunity to promote persistence, through modulation of cytokine responses, immune cell recruitment, and macrophage polarization in murine models of infection. By uncovering how s. Aureus persisters both evade and reshape innate immunity, this work will provide novel insight into the biological basis of staphylococcal persistence and illuminate why these infections remain so difficult to eradicate.