Trained immunity in recurrent Staphylococcus aureus infection promotes bacterial persistence

• Published in: PLoS pathogens Vol. 20; no. 1; p. e1011918
• Main Authors: Lin, Xiao-Qi, Liu, Zhen-Zhen, Zhou, Cheng-Kai, Zhang, Liang, Gao, Yu, Luo, Xue-Yue, Zhang, Jian-Gang, Chen, Wei, Yang, Yong-Jun
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.01.2024; Public Library of Science (PLoS)
• Subjects: Analysis; Antibiotics; Bacteria; Bacterial diseases; Bacterial infections; Care and treatment; Diagnosis; Disease susceptibility; Diseases; Drug resistance; Drug resistance in microorganisms; Epidemiology; Immunity; Infection; Infection control; Mastitis; Medical research; Medicine, Experimental; Metformin; Prevention; Public health; Recurrent infection; Relapse; Rifampin; Risk factors; Secondary infection; Skin diseases; Staphylococcus aureus; Staphylococcus aureus infections; Staphylococcus infections; Tetracycline; Tetracyclines; Therapeutic targets; Variance analysis; China
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1011918

Bacterial persister cells, a sub-population of dormant phenotypic variants highly tolerant to antibiotics, present a significant challenge for infection control. Investigating the mechanisms of antibiotic persistence is crucial for developing effective treatment strategies. Here, we found a significant association between tolerance frequency and previous infection history in bovine mastitis. Previous S . aureus infection led to S . aureus tolerance to killing by rifampicin in subsequent infection in vivo and in vitro. Actually, the activation of trained immunity contributed to rifampicin persistence of S . aureus in secondary infection, where it reduced the effectiveness of antibiotic treatment and increased disease severity. Mechanically, we found that S . aureus persistence was mediated by the accumulation of fumarate provoked by trained immunity. Combination therapy with metformin and rifampicin promoted eradication of persisters and improved the severity of recurrent S . aureus infection. These findings provide mechanistic insight into the relationship between trained immunity and S . aureus persistence, while providing proof of concept that trained immunity is a therapeutic target in recurrent bacterial infections involving persistent pathogens.