Table 1.

S. pneumoniae-derived virulence factors and their modes of action in contributing to CNS invasion, and BBB transmigration and dysfunction in PM.

	Virulence Factor	Mode(s) of Action	Reference(s)
Capsule	Thick polysaccharide capsule	Reduce neutrophil extracellular trapping	[43]
		Reduce phagocytosis	[44]
		Reduce complement deposition	[45]
	Thin polysaccharide capsule	Expose pneumococcal surface protein binding sites	[43,44,45]
Pili	Pneumococcal pilus-1	Increase attachment to endothelial cells	[51]
	Pilus adhesin RrgA	Facilitates BBB translocation through pIgR and PECAM-1 binding	[51]
Choline binding proteins	Pneumococcal surface protein A (PspA)	Interferes with complement factor B	[53]
		Inhibits human apo-lactoferrin activity	[56]
	Choline-binding protein A (CbpA)	Inactivates C3b through complementary factor H binding	[54,55]
		Facilitates BBB translocation through plgR and PAF receptors on endothelial cells	[38,51,60]
Cell wall	Peptidoglycan	Activates host TLR, increasing inflammation	[66]
	Teichoic Acid	Binds choline-binding proteins to pneumococcal cell wall	[36]
		Activates host TLR, increasing inflammation	[66]
Pneumococcal surface proteins	Neuraminidase A	Cleaves N-acetylneuraminic acid	[67]
		Facilitates endothelial binding through LGLD	[52]
Secreted	Pneumococcal IgA protease	Cleaves host secretory IgA	[68]
	Hyaluronidase	Degrades hyaluronan	[69]
	Pneumococcal phospholipase A2 (PLA2)	Increases inflammation	[63]
		Associated with upregulation of endothelial cell adhesins	[65]
	Hydrogen peroxide	Kills competing microbes	[71]
	Pneumolysin	Cytolytic through ply pore formation to epithelial, endothelial and glial cells	[74,81,82,83,84]
		Stimulates complement pathways	[75]
		Activates TLR and NLR inflammasome pathways	[76,77]
		Activates NADPH oxidase	[78]
		Activates ROS production in neutrophils	[78]
		Disrupts ependymal cilia	[79,80]

BBB—blood‒brain barrier, IgA—immunoglobin A, NADPH—nicotinamide adenine dinucleotide phosphate, NLR—NOD-like receptor, PAF—platelet-activating factor, PECAM-1—platelet endothelial cell adhesion molecule-1, plgR—poly immunoglobin receptor, ply—pneumolysin, Psp—pneumococcal surface protein, RgrA—pilus-related adhesin, ROS—reactive oxygen species, TLR—toll-like receptor.