title: The surface-anchored NanA protein promotes pneumococcal brain endothelial cell invasion.
abstract: In humans, Streptococcus pneumoniae (SPN) is the leading cause of bacterial meningitis, a disease with high attributable mortality and frequent permanent neurological sequelae. The molecular mechanisms underlying the central nervous system tropism of SPN are incompletely understood, but include a primary interaction of the pathogen with the blood-brain barrier (BBB) endothelium. All SPN strains possess a gene encoding the surface-anchored sialidase (neuraminidase) NanA, which cleaves sialic acid on host cells and proteins. Here, we use an isogenic SPN NanA-deficient mutant and heterologous expression of the protein to show that NanA is both necessary and sufficient to promote SPN adherence to and invasion of human brain microvascular endothelial cells (hBMECs). NanA-mediated hBMEC invasion depends only partially on sialidase activity, whereas the N-terminal lectinlike domain of the protein plays a critical role. NanA promotes SPN-BBB interaction in a murine infection model, identifying the protein as proximal mediator of CNS entry by the pathogen.
authors.affiliation: Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Uchiyama
authors.forename: Aaron F
authors.initials: AF
authors.lastname: Carlin
authors.forename: Arya
authors.initials: A
authors.lastname: Khosravi
authors.forename: Shannon
authors.initials: S
authors.lastname: Weiman
authors.forename: Anirban
authors.initials: A
authors.lastname: Banerjee
authors.forename: Darin
authors.initials: D
authors.lastname: Quach
authors.forename: George
authors.initials: G
authors.lastname: Hightower
authors.forename: Tim J
authors.initials: TJ
authors.lastname: Mitchell
authors.forename: Kelly S
authors.initials: KS
authors.lastname: Doran
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000382:microbiology*; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D017931:DNA Primers / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism*; D006801:Humans; D008297:Male; D016920:Meningitis, Bacterial / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D019158:N-Acetylneuraminic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D009439:Neuraminidase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010957:Plasmids / Q000235:genetics; D013296:Streptococcus pneumoniae / Q000235:genetics / Q000378:metabolism*
chemical_list: D017931:DNA Primers; C036137:2-deoxy-2,3-dehydro-N-acetylneuraminic acid; D009439:Neuraminidase; D019158:N-Acetylneuraminic Acid
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