A streptococcal Fic domain-containing protein disrupts blood-brain barrier integrity by activating moesin in endothelial cells

• Published in: PLoS pathogens Vol. 15; no. 5; p. e1007737
• Main Authors: Ma, Zhe, Peng, Jie, Yu, Dandan, Park, Joseph S, Lin, Huixing, Xu, Bin, Lu, Chengping, Fan, Hongjie, Waldor, Matthew K
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 09.05.2019; Public Library of Science (PLoS)
• Subjects: Activation; Agriculture; Animals; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Bacteriology; Biological Transport; Biology and Life Sciences; Blood-brain barrier; Blood-Brain Barrier - metabolism; Blood-Brain Barrier - microbiology; Blood-Brain Barrier - pathology; Brain; Brain - metabolism; Brain - microbiology; Brain - pathology; Brain research; C-Terminus; Cell Membrane Permeability; Cells, Cultured; Cytoskeleton; Depletion; Disease prevention; Disruption; Endothelial cells; Endothelium; Endothelium, Vascular - metabolism; Endothelium, Vascular - microbiology; Endothelium, Vascular - pathology; Female; Food safety; Funding; Genetic aspects; Hospitals; Humans; Infectious diseases; Integrity; Kinases; Laboratories; Medical schools; Medicine and Health Sciences; Meningitis; Mice; Mice, Inbred BALB C; Microfilament Proteins - metabolism; Microvasculature; Moesin; Monolayers; Pathogenic microorganisms; Pathogens; Permeability; Phosphorylation; Physical Sciences; Physiological aspects; Proteins; Research and Analysis Methods; RhoA protein; Software; Streptococcus; Streptococcus - physiology; Supervision; Translocation; Veterinary colleges; Veterinary medicine; Virulence; Womens health; Zoonoses; United States > US; China; Massachusetts
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1007737

Streptococcus equi subsp. zooepidemicus (SEZ) is a zoonotic pathogen capable of causing meningitis in humans. The mechanisms that enable pathogens to traverse the blood-brain barrier (BBB) are incompletely understood. Here, we investigated the role of a newly identified Fic domain-containing protein, BifA, in SEZ virulence. BifA was required for SEZ to cross the BBB and to cause meningitis in mice. BifA also enhanced SEZ translocation across human Brain Microvascular Endothelial Cell (hBMEC) monolayers. Purified BifA or its Fic domain-containing C-terminus alone were able to enter into hBMECs, leading to disruption of monolayer barrier integrity. A SILAC-based proteomic screen revealed that BifA binds moesin. BifA's Fic domain was required for its binding to this regulator of host cell cytoskeletal processes. BifA treatment of hBMECs led to moesin phosphorylation and downstream RhoA activation. Inhibition of moesin activation or moesin depletion in hBMEC monolayers abrogated BifA-mediated increases in barrier permeability and SEZ's capacity to translocate across monolayers. Thus, BifA activation of moesin appears to constitute a key mechanism by which SEZ disrupts endothelial monolayer integrity to penetrate the BBB.