Outer membrane protein A mediates Klebsiella pneumoniae penetration of the blood-brain barrier and induces bacterial meningitis

Weiliang Zeng; Yao Sun; Jia Zhang; Zhuocheng Yao; Jianming Cao; Panjie Hu; Changrui Qian; Jian Li; Tieli Zhou

doi:10.1016/j.micres.2025.128262

Outer membrane protein A mediates Klebsiella pneumoniae penetration of the blood-brain barrier and induces bacterial meningitis

Microbiol Res. 2025 Jun 23:299:128262. doi: 10.1016/j.micres.2025.128262. Online ahead of print.

Authors

Weiliang Zeng¹, Yao Sun¹, Jia Zhang², Zhuocheng Yao¹, Jianming Cao³, Panjie Hu¹, Changrui Qian¹, Jian Li⁴, Tieli Zhou⁵

Affiliations

¹ Department of Clinical Laboratory, Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China.
² School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, Zhejiang Province, China.
³ Department of Clinical Laboratory, Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China; School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, Zhejiang Province, China.
⁴ Biomedicine Discovery Institute, Infection Program, Department of Microbiology, Monash University, Melbourne, VIC 3800, Australia; Monash Biomedicine Discovery Institute-Wenzhou Medical University Alliance in Clinical and Experimental Biomedicine, Monash University, Clayton, VIC, Australia. Electronic address: jian.li@monash.edu.
⁵ Department of Clinical Laboratory, Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China; Monash Biomedicine Discovery Institute-Wenzhou Medical University Alliance in Clinical and Experimental Biomedicine, Monash University, Clayton, VIC, Australia. Electronic address: wyztli@163.com.

PMID: 40578143
DOI: 10.1016/j.micres.2025.128262

Abstract

Klebsiella pneumoniae is an important meningeal pathogen. Penetration of the blood-brain barrier (BBB) is a prerequisite for K. pneumoniae meningitis, although the underlying mechanisms remain unclear. Our study found that outer membrane protein A (OmpA), a virulence factor of K. pneumoniae, facilitates BBB penetration and induces K. pneumoniae meningitis. Experimental results revealed that the mucoviscosity, biofilm formation, capsular polysaccharide production, serum resistance, in vitro competitiveness, and motarlity rates in Galleria mellonella were markedly reduced in an ompA deletion strain (FK3907 ΔompA). In a mouse meningitis model, significant reductions in bacterial loads, mortality rate, clinical symptoms, and brain tissue damage were observed in mice infected with FK3907 ΔompA compared to FK3907 (wild-type) and FK3907 ΔompA+ompA strains. Furthermore, the wild-type strain demonstrated a markedly enhanced ability to disrupt the BBB both in vitro and in vivo compared to the FK3907 ΔompA strain. This enhancement involved not only the rearrangement of F-actin in bEnd.3 cells but also the activation of an inflammatory cytokine storm. Importantly, the wild-type strain exhibited significantly enhanced adhesion, invasion, and intracellular proliferation within RAW264.7 cells. A wound healing assay indicated that wild-type strain promoted RAW264.7 cell migration. Collectively, we identified OmpA as a required virulence factor and essential pathogenic factor for K. pneumoniae. It promotes K. pneumoniae penetration BBB via transcellular pathway, trojan horse pathway, and pro-inflammatory pathway. Our study improves an in-depth understanding for K. pneumoniae penetration BBB from the perspective of bacterial-host interactions, highlighting OmpA as a potential target for intervention in K. pneumoniae meningitis.

Keywords: Bacterial meningitis; Blood-brain barrier; Klebsiella pneumoniae; Outer membrane protein A; Pathogenicity.