Membrane vesicle delivery of a streptococcal M protein disrupts the blood–brain barrier by inducing autophagic endothelial cell death

Abstract

M family proteins are critical virulence determinants of Streptococci. Streptococcus equi subsp. zooepidemicus (SEZ) are Group C streptococci that cause meningitis in animals and humans. SzM, the M protein of SEZ, has been linked to SEZ brain invasion. Here, we demonstrate that SzM is important in SEZ disruption of the blood–brain barrier (BBB). SEZ release SzM-bound membrane vesicles (MVs), and endocytosis of these vesicles by human brain endothelial microvascular cells (hBMECs) results in SzM-dependent cytotoxicity. Furthermore, administration of SzM-bound MVs disrupted the murine BBB. A CRISPR screen revealed that SzM cytotoxicity in hBMECs depends on PTEN-related activation of autophagic cell death. Pharmacologic inhibition of PTEN activity prevented SEZ disruption of the murine BBB and delayed mortality. Our data show that MV delivery of SzM to host cells plays a key role in SEZ pathogenicity and suggests that MV delivery of streptococcal M family proteins is likely a common streptococcal virulence mechanism.

Streptococcus pneumoniae extracellular vesicles aggravate alveolar epithelial barrier disruption via autophagic degradation of OCLN (occludin)

“…S1G). Additionally, it has been suggested that bacteria can actively form OMVs or EVs as transport vehicles to deliver virulence factors to host cells [ 11 , 44 ]. Therefore, we speculated whether S. pneumoniae relied on EVs to deliver some kind of virulence factor involved in the activation of autophagy.…”

“…Previous studies have reported that bacteria-released pEVs can inherit pathogen-associated molecular patterns of bacteria, and can be effectively recognized and internalized by host cells via endocytosis [ 11 , 46 ]. Alveolar epithelial cells, the first line of defense against pathogens, play a critical role in preventing bacteria from entering the bloodstream [ 47 , 48 ].…”

“…Recent studies have provided evidence that gram-positive bacteria can also release spherical membrane particles from the cell surface, referred to as extracellular vesicles (EVs) [ 10 ]. These EVs have been found to play a role in host-pathogen interactions by delivering bacterial components into host cells, which causes cytotoxic effects, and thus increases bacterial pathogenicity [ 11–16 ]. For example, EVs derived from Staphylococcus aureus ( S. aureus ) have been shown to activate toll-like receptors and induce pro-inflammatory cytokine responses in epithelial cells [ 12 ] and macrophages [ 17 ].…”

“…For example, EVs derived from Staphylococcus aureus ( S. aureus ) have been shown to activate toll-like receptors and induce pro-inflammatory cytokine responses in epithelial cells [ 12 ] and macrophages [ 17 ]. Although the internalization of EVs into epithelial and endothelial cells has been observed to increase barrier permeability [ 11 ], there is still a lack of evidence on how EVs disrupt AEB integrity.…”

Astrocyte‐Derived Extracellular Vesicular miR‐143‐3p Dampens Autophagic Degradation of Endothelial Adhesion Molecules and Promotes Neutrophil Transendothelial Migration after Acute Brain Injury

“…In a physiological state, BMECs act as a gatekeeper, blocking the entry of toxins, pathogens, and peripheral circulating cells into brain. [ 3,4 ] However, early after the onset of an acute brain injury like intracerebral hemorrhage (ICH) and traumatic brain injury (TBI), BMECs typically undergo activation and exhibit heightened expression of inflammatory cell adhesion molecules (CAMs) including ICAM‐1, VCAM‐1, PECAM‐1 and E‐selectin. [ 5–7 ] CAMs play a pivotal role in the adhesion of circulating immune cells to the inflamed BMECs, thereby facilitating their transmigration across the endothelial barrier into the brain.…”