pIgR and PECAM-1 bind to pneumococcal adhesins RrgA and PspC mediating bacterial brain invasion

Area of Science:

• Microbiology
• Neuroscience
• Immunology

Background:

• Streptococcus pneumoniae is a leading cause of bacterial meningitis.
• Meningitis is life-threatening with high fatality rates despite antibiotic treatment.
• Pneumococci invade the bloodstream and breach the blood-brain barrier (BBB) to cause meningitis.

Purpose of the Study:

• To investigate the mechanisms of pneumococcal invasion across the BBB.
• To identify specific bacterial adhesins and host receptors involved in meningitis pathogenesis.
• To evaluate therapeutic strategies targeting these interactions for meningitis prevention.

Main Methods:

• Stimulated emission depletion (STED) super-resolution microscopy of human brain biopsies.
• In vitro binding assays using pneumococcal adhesins (RrgA, PspC) and endothelial receptors (pIgR, PECAM-1).
• In vivo studies using a mouse model of pneumococcal meningitis and receptor-blocking antibodies.

Main Results:

• Pneumococci colocalize with pIgR and PECAM-1 at the BBB in human meningitis cases.
• Pneumococcal adhesin RrgA binds both pIgR and PECAM-1; PspC binds pIgR.
• Antibodies against pIgR and PECAM-1 prevented pneumococcal brain entry and meningitis in mice.
• Combined antibody and antibiotic treatment further reduced bacterial brain burden.

Conclusions:

• pIgR and PECAM-1 are critical host receptors for pneumococcal meningitis.
• Targeting these receptors offers a promising strategy to prevent pneumococcal meningitis.
• Inhibition of pIgR and PECAM-1, alongside antibiotics, enhances therapeutic efficacy.