Within-host evolution of a transcriptional regulator contributes to the establishment of chronic Pseudomonas aeruginosa infection

Ning Zhou; Jingchen Yu; Xujiao Liu; Chengxi Li; Huang Tang; Lin Lyu; Chengwei Wu; Yana Chen; Jian Zhang; Jinjing Ni; Danni Wang; Jing Tao; Wenjuan Wu; Yu Zhang; Yun Feng; Yanjie Chao; Jie Lu; Ping He; Yu-Feng Yao

doi:10.1016/j.celrep.2024.115214

Within-host evolution of a transcriptional regulator contributes to the establishment of chronic Pseudomonas aeruginosa infection

Cell Rep. 2025 Jan 17;44(1):115214. doi: 10.1016/j.celrep.2024.115214. Online ahead of print.

Authors

Ning Zhou¹, Jingchen Yu¹, Xujiao Liu², Chengxi Li³, Huang Tang¹, Lin Lyu¹, Chengwei Wu⁴, Yana Chen⁵, Jian Zhang⁴, Jinjing Ni¹, Danni Wang¹, Jing Tao¹, Wenjuan Wu⁶, Yu Zhang², Yun Feng⁷, Yanjie Chao⁸, Jie Lu⁹, Ping He¹⁰, Yu-Feng Yao¹¹

Affiliations

¹ Laboratory of Bacterial Pathogenesis, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
² Key Laboratory of Synthetic Biology, Center for Excellence in Molecular Plant Sciences, Shanghai Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai 200032, China.
³ Anhui Key Laboratory of Infection and Immunity, Department of Microbiology and Parasitology, Bengbu Medical College, Bengbu, Anhui 233030, China.
⁴ Medicinal Chemistry and Bioinformatics Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
⁵ Department of Pediatrics, Anhui Provincial Hospital, The First Affiliated Hospital of USTC, Hefei, Anhui 230001, China.
⁶ Department of Laboratory Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200123, China.
⁷ Department of Pulmonary and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
⁸ Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai 200031, China.
⁹ Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: [email protected].
¹⁰ Department of Microbiology and Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: [email protected].
¹¹ Laboratory of Bacterial Pathogenesis, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Department of Microbiology and Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; State Key Laboratory of Microbial Metabolism, and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China; Shanghai Key Laboratory of Emergency Prevention, Diagnosis and Treatment of Respiratory Infectious Diseases (20dz2261100), Shanghai 200025, China. Electronic address: [email protected].

PMID: 39826124
DOI: 10.1016/j.celrep.2024.115214

Abstract

As an opportunistic pathogen, Pseudomonas aeruginosa can cause both acute and chronic infections that are notoriously difficult to treat. However, the mechanism underlying acute or chronic P. aeruginosa infection remains unclear. Here, we identify a mutation in a transcriptional regulator PA5438 (named GavR). This mutation causes a 3-amino-acid absence in GavR and is strongly associated with chronic P. aeruginosa infection. Mechanistically, the deletion in GavR directly downregulates the transcription of the aceEF operon and leads to an accumulation of intracellular pyruvate, which can promote bacterial survival in neutrophils. Notably, P. aeruginosa with 9-bp-deleted or full-length gavR composes a mixed population in most patients with chronic or acute infections. Overall, the mutation in gavR attenuates P. aeruginosa virulence and enhances innate immune evasion by reprogramming pyruvate metabolism and the glyoxylate cycle. This work reveals a molecular mechanism of transition control from acute to chronic infection in P. aeruginosa.

Keywords: CP: Metabolism; CP: Microbiology; GavR; Pseudomonas aeruginosa; RccR; chronic infection; metabolism; transcriptional regulator.