2. Academic Validation
  3. Meningitic Escherichia coli α-hemolysin aggravates blood-brain barrier disruption via targeting TGFβ1-triggered hedgehog signaling

Meningitic Escherichia coli α-hemolysin aggravates blood-brain barrier disruption via targeting TGFβ1-triggered hedgehog signaling

  • Mol Brain. 2021 Jul 19;14(1):116. doi: 10.1186/s13041-021-00826-2.
Jiyang Fu 1 2,  Liang Li 1 2,  Dong Huo 1 2,  Ruicheng Yang 1 2,  Bo Yang 1 2,  Bojie Xu 1 2,  Xiaopei Yang 3,  Menghong Dai 1 2,  Chen Tan 1 2 4 5,  Huanchun Chen 1 2 4 5,  Xiangru Wang 6 7 8 9
Affiliations

Affiliations

  • 1 State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, China.
  • 2 Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, Hubei, China.
  • 3 Wuhan Animal Disease Control Center, Wuhan, Hubei, China.
  • 4 Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture of the People's Republic of China, Wuhan, Hubei, China.
  • 5 International Research Center for Animal Disease, Ministry of Science and Technology of the People's Republic of China, Wuhan, Hubei, China.
  • 6 State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, China. wangxr228@mail.hzau.edu.cn.
  • 7 Key Laboratory of Preventive Veterinary Medicine in Hubei Province, The Cooperative Innovation Center for Sustainable Pig Production, Wuhan, Hubei, China. wangxr228@mail.hzau.edu.cn.
  • 8 Key Laboratory of Development of Veterinary Diagnostic Products, Ministry of Agriculture of the People's Republic of China, Wuhan, Hubei, China. wangxr228@mail.hzau.edu.cn.
  • 9 International Research Center for Animal Disease, Ministry of Science and Technology of the People's Republic of China, Wuhan, Hubei, China. wangxr228@mail.hzau.edu.cn.
PMID: 34281571 DOI: 10.1186/s13041-021-00826-2
Abstract

Bacterial meningitis is a life-threatening infectious disease with severe neurological sequelae and a high mortality rate, in which Escherichia coli is one of the primary Gram-negative etiological bacteria. Meningitic E. coli Infection is often accompanied by an elevated blood-brain barrier (BBB) permeability. BBB is the structural and functional barrier composed of brain microvascular endothelial cells (BMECs), astrocytes, and pericytes, and we have previously shown that astrocytes-derived TGFβ1 physiologically maintained the BBB permeability by triggering a non-canonical Hedgehog signaling in brain microvascular endothelial cells (BMECs). Here, we subsequently demonstrated that meningitic E. coli Infection could subvert this intercellular communication within BBB by attenuating TGFBRII/Gli2-mediated such signaling. By high-throughput screening, we identified E. coli α-hemolysin as the critical determinant responsible for this attenuation through Sp1-dependent TGFBRII reduction and triggering CA2+ influx and protein kinase A activation, thus leading to Gli2 suppression. Additionally, the exogenous Hedgehog agonist SAG exhibited promising protection against the infection-caused BBB dysfunction. Our work revealed a hedgehog-targeted pathogenic mechanism during meningitic E. coli-caused BBB disruption and suggested that activating Hedgehog signaling within BBB could be a potential protective strategy for future therapy of Bacterial meningitis.

Keywords

Blood–brain barrier; Escherichia coli; Hedgehog signaling; Intercellular communication; TGFβ1; α-Hemolysin.

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