title: Modulation of connexin expression and gap junction communication in astrocytes by the gram-positive bacterium S. aureus.
abstract: Gap junctions establish direct intercellular conduits between adjacent cells and are formed by the hexameric organization of protein subunits called connexins (Cx). It is unknown whether the proinflammatory milieu that ensues during CNS infection with S. aureus, one of the main etiologic agents of brain abscess in humans, is capable of eliciting regional changes in astrocyte homocellular gap junction communication (GJC) and, by extension, influencing neuron homeostasis at sites distant from the primary focus of infection. Here we investigated the effects of S. aureus and its cell wall product peptidoglycan (PGN) on Cx43, Cx30, and Cx26 expression, the main Cx isoforms found in astrocytes. Both bacterial stimuli led to a time-dependent decrease in Cx43 and Cx30 expression; however, Cx26 levels were elevated following bacterial exposure. Functional examination of dye coupling, as revealed by single-cell microinjections of Lucifer yellow, demonstrated that both S. aureus and PGN inhibited astrocyte GJC. Inhibition of protein synthesis with cyclohexamide (CHX) revealed that S. aureus directly modulates, in part, Cx43 and Cx30 expression, whereas Cx26 levels appear to be regulated by a factor(s) that requires de novo protein production; however, CHX did not alter the inhibitory effects of S. aureus on astrocyte GJC. The p38 MAPK inhibitor SB202190 was capable of partially restoring the S. aureus-mediated decrease in astrocyte GJC to that of unstimulated cells, suggesting the involvement of p38 MAPK-dependent pathway(s). These findings could have important implications for limiting the long-term detrimental effects of abscess formation in the brain which may include seizures and cognitive deficits.
authors.affiliation: Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
authors.forename: Nilufer
authors.initials: N
authors.lastname: Esen
authors.forename: Debbie
authors.initials: D
authors.lastname: Shuffield
authors.forename: Mohsin M D
authors.initials: MM
authors.lastname: Syed
authors.forename: Tammy
authors.initials: T
authors.lastname: Kielian
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000378:metabolism* / Q000382:microbiology* / Q000503:physiopathology; D001922:Brain Abscess / Q000378:metabolism / Q000503:physiopathology; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D018920:Coculture Techniques; D000072259:Connexin 26; D000075302:Connexin 30; D018031:Connexin 43 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D017630:Connexins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D017629:Gap Junctions / Q000187:drug effects / Q000378:metabolism*; D007546:Isoquinolines; D051379:Mice; D008810:Mice, Inbred C57BL; D010457:Peptidoglycan / Q000378:metabolism / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D013203:Staphylococcal Infections / Q000378:metabolism / Q000503:physiopathology; D013211:Staphylococcus aureus / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000075302:Connexin 30; D018031:Connexin 43; D017630:Connexins; C000607042:GJB2 protein, human; C100629:Gjb6 protein, mouse; D007546:Isoquinolines; D010457:Peptidoglycan; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D000072259:Connexin 26; C017475:lucifer yellow; D048051:p38 Mitogen-Activated Protein Kinases