Pneumococcal neuraminidase activates TGF-β signalling.

Area of Science:

• Microbiology
• Immunology
• Cell Biology

Background:

• Neuraminidase A (NanA) is a pneumococcal virulence factor anchored to the cell wall.
• A secreted NanA allele is over-represented in invasive isolates and linked to meningitis development.

Purpose of the Study:

• To investigate the role of NanA secretion versus cell-wall anchoring in pneumococcal meningitis.
• To elucidate the molecular mechanisms by which NanA affects blood-brain barrier integrity and bacterial invasion.

Main Methods:

• Comparative analysis of secreted and cell-wall anchored NanA alleles.
• In vitro assays using recombinant NanA and whole bacteria.
• Assessment of transforming growth factor (TGF)-β signaling, SMAD signaling, and endothelial tight junction ZO-1 expression.

Main Results:

• Both secreted and cell-bound NanA activated TGF-β and SMAD signaling, leading to ZO-1 loss.
• Only cell-bound NanA decreased ZO-1 expression in whole bacteria assays.
• NanA-dependent bacterial invasion of endothelial cells was observed.

Conclusions:

• NanA secretion versus cell-surface retention does not influence neurotropism.
• A novel NanA-TGF-β signaling axis decreases blood-brain barrier integrity.
• This axis enhances bacterial invasion, contributing to meningitis pathogenesis.