International immunopharmacology · 2025
Type I and II pili mediate Streptococcus pneumoniae invasion into human blood-brain barrier-derived cells through extracellular matrix protein receptors and different endocytosis pathways.
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Chen Sui-Ning, Wang Yu-Jin, Li Meng-Jie, Xing Yi-Qiong, Guo Meng-Yi, Yan Jie, Sun Ai-Hua
Аннотация
BACKGROUD: Streptococcus pneumoniae is the most common pathogen of bacterial meningitis, but mechanisms of this pathogen invading blood-brain barrier (BBB) remain unknown.
METHODS: Invasion of S. pneumoniae strains and microbeads coated with recombinant pilin, rRrgA-B or rPitB, into human BBB-derived brain microvascular endothelial cells (HBMECs), brain vascular pericytes (HBVPs), and astrocytes (HAs) by laser scanning confocal microscopy (LSCM). Fibronectin (FN), laminin (LN), and collagen-1/3/4 (COL-1/3/4) in the extracellular matrix (ECM) were detected by LSCM and flow cytometry. rRrgA-B and rPitB binding to the ECM proteins were identified using surface plasmon resonance. Pneumococcal endocytosis pathways, Ca2+ level, microfilament (MF) and microtubule (MT) polymerization in the cells were determined by LSCM-based inhibition assay.
RESULTS: Type I/II pili-positive S. pneumoniae SP007 displayed natably stronger invasiveness into the cells than pilus-free S. pneumoniae ATCC49619. rRrgA-B-/rPitB-coated microbeads also exhibited invasion ability. HBMECs express FN, LN, and COL1, while HBVPs and HAs express all the ECM proteins. rRrgA-B and rPitB displayed a rapid binding to all the ECM proteins with KD values ranging from 3.25 × 10-7 to 9.58 × 10-8 M. Intracellular free Ca2+ increase and MF-dependent cytoskeleton rearrangement occurred during invasion of the pneumococcal strains and rRrgA-B-/rPitB-coated microbeads. Invasion of the strains and rRrgA-B-/rPitB-coated microbeads into these cells involved integrin (ITG), focal adhesion kinase (FAK), Rho-associated coiled-coil forming kinase (ROCK) or phosphatidylinositol-3-kinase (PI3K), clathrin (CLN)-, caveolae (CAV)- or macropinocytosis (MPC)-dependent endocytosis.
CONCLUSION: Type I and II pili play important roles to mediate S. pneumoniae invasion into BBB-direived cells through FN/LN/COL1-ITG-FAK/ROCK-Ca2+-MF-CLN/CAV/MPC- or FN/LN/COL1/3/4-ITG-FAK/PI3K-Ca2+-MF-CLN/CAV-dependent endocytosis pathways to cause meningitis.
METHODS: Invasion of S. pneumoniae strains and microbeads coated with recombinant pilin, rRrgA-B or rPitB, into human BBB-derived brain microvascular endothelial cells (HBMECs), brain vascular pericytes (HBVPs), and astrocytes (HAs) by laser scanning confocal microscopy (LSCM). Fibronectin (FN), laminin (LN), and collagen-1/3/4 (COL-1/3/4) in the extracellular matrix (ECM) were detected by LSCM and flow cytometry. rRrgA-B and rPitB binding to the ECM proteins were identified using surface plasmon resonance. Pneumococcal endocytosis pathways, Ca2+ level, microfilament (MF) and microtubule (MT) polymerization in the cells were determined by LSCM-based inhibition assay.
RESULTS: Type I/II pili-positive S. pneumoniae SP007 displayed natably stronger invasiveness into the cells than pilus-free S. pneumoniae ATCC49619. rRrgA-B-/rPitB-coated microbeads also exhibited invasion ability. HBMECs express FN, LN, and COL1, while HBVPs and HAs express all the ECM proteins. rRrgA-B and rPitB displayed a rapid binding to all the ECM proteins with KD values ranging from 3.25 × 10-7 to 9.58 × 10-8 M. Intracellular free Ca2+ increase and MF-dependent cytoskeleton rearrangement occurred during invasion of the pneumococcal strains and rRrgA-B-/rPitB-coated microbeads. Invasion of the strains and rRrgA-B-/rPitB-coated microbeads into these cells involved integrin (ITG), focal adhesion kinase (FAK), Rho-associated coiled-coil forming kinase (ROCK) or phosphatidylinositol-3-kinase (PI3K), clathrin (CLN)-, caveolae (CAV)- or macropinocytosis (MPC)-dependent endocytosis.
CONCLUSION: Type I and II pili play important roles to mediate S. pneumoniae invasion into BBB-direived cells through FN/LN/COL1-ITG-FAK/ROCK-Ca2+-MF-CLN/CAV/MPC- or FN/LN/COL1/3/4-ITG-FAK/PI3K-Ca2+-MF-CLN/CAV-dependent endocytosis pathways to cause meningitis.