{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T02:16:22Z","timestamp":1792289782018,"version":"4.4.0"},"reference-count":80,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2009,2,1]],"date-time":"2009-02-01T00:00:00Z","timestamp":1233446400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,2,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Staphylococcus aureus and Streptococcus pyogenes colonize mucosal surfaces of the human body to cause disease. A group of virulence factors known as superantigens are produced by both of these organisms that allows them to cause serious diseases from the vaginal (staphylococci) or oral mucosa (streptococci) of the body. Superantigens interact with T cells and APCs to cause massive cytokine release to mediate the symptoms collectively known as toxic shock syndrome. In this study we demonstrate that another group of virulence factors, cytolysins, aid in the penetration of superantigens across vaginal mucosa as a representative nonkeratinized stratified squamous epithelial surface. The staphylococcal cytolysin \u03b1-toxin and the streptococcal cytolysin streptolysin O enhanced penetration of toxic shock syndrome toxin-1 and streptococcal pyrogenic exotoxin A, respectively, across porcine vaginal mucosa in an ex vivo model of superantigen penetration. Upon histological examination, both cytolysins caused damage to the uppermost layers of the vaginal tissue. In vitro evidence using immortalized human vaginal epithelial cells demonstrated that although both superantigens were proinflammatory, only the staphylococcal cytolysin \u03b1-toxin induced a strong immune response from the cells. Streptolysin O damaged and killed the cells quickly, allowing only a small release of IL-1\u03b2. Two separate models of superantigen penetration are proposed: staphylococcal \u03b1-toxin induces a strong proinflammatory response from epithelial cells to disrupt the mucosa enough to allow for enhanced penetration of toxic shock syndrome toxin-1, whereas streptolysin O directly damages the mucosa to allow for penetration of streptococcal pyrogenic exotoxin A and possibly viable streptococci.<\/jats:p>","DOI":"10.4049\/jimmunol.0803283","type":"journal-article","created":{"date-parts":[[2009,2,9]],"date-time":"2009-02-09T12:02:33Z","timestamp":1234180953000},"page":"2364-2373","source":"Crossref","is-referenced-by-count":53,"title":["Cytolysins Augment Superantigen Penetration of Stratified Mucosa"],"prefix":"10.1093","volume":"182","author":[{"given":"Amanda J","family":"Brosnahan","sequence":"first","affiliation":[{"name":"Department of Microbiology, University of Minnesota Medical School , Minneapolis, MN 55455"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary J","family":"Mantz","sequence":"additional","affiliation":[{"name":"Dows Institute for Dental Research, College of Dentistry, University of Iowa , Iowa City, IA 52246"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher A","family":"Squier","sequence":"additional","affiliation":[{"name":"Dows Institute for Dental Research, College of Dentistry, University of Iowa , Iowa City, IA 52246"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marnie L","family":"Peterson","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Pharmacology, University of Minnesota College of Pharmacy , Minneapolis, MN 55455"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick M","family":"Schlievert","sequence":"additional","affiliation":[{"name":"Department of Microbiology, University of Minnesota Medical School , Minneapolis, MN 55455"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2009,2,15]]},"reference":[{"key":"2026012806233338300_R1","first-page":"146","article-title":"Clinical and bacteriologic observations of a toxic shock-like syndrome due to Streptococcus pyogenes.","volume-title":"N. Engl. J. Med.","year":"1987"},{"key":"2026012806233338300_R2","first-page":"1116","article-title":"Toxic-shock syndrome associated with phage-group-I staphylococci.","volume-title":"Lancet","year":"1978"},{"key":"2026012806233338300_R3","first-page":"1429","article-title":"Toxic-shock syndrome: epidemiologic features, recurrence, risk factors, and prevention.","volume-title":"N. Engl. J. Med.","year":"1980"},{"key":"2026012806233338300_R4","first-page":"1436","article-title":"Toxic-shock syndrome in menstruating women: association with tampon use and Staphylococcus aureus and clinical features in 52 cases.","volume-title":"N. Engl. J. Med.","year":"1980"},{"key":"2026012806233338300_R5","first-page":"1398","article-title":"An immunogenetic and molecular basis for differences in outcomes of invasive group A streptococcal infections.","volume-title":"Nat. Med.","year":"2002"},{"key":"2026012806233338300_R6","first-page":"1","article-title":"Severe group A streptococcal infections associated with a toxic shock-like syndrome and scarlet fever toxin A.","volume-title":"N. Engl. J. Med.","year":"1989"},{"key":"2026012806233338300_R7","first-page":"47","article-title":"Toxins and superantigens of group A streptococci. R. P. Novick, and V. A. Fischetti, and J. J. Ferretti, and D. A. Portnoy, and J. I. Rood, eds.","volume-title":"Gram Positive Pathogens","year":"2006"},{"key":"2026012806233338300_R8","first-page":"467","article-title":"Reinterpretation of the Dick test: role of group A streptococcal pyrogenic exotoxin.","volume-title":"Infect. Immun.","year":"1979"},{"key":"2026012806233338300_R9","first-page":"271","article-title":"Streptococcal toxic shock syndrome associated with necrotizing fasciitis.","volume-title":"Annu. Rev. Med.","year":"2000"},{"key":"2026012806233338300_R10","first-page":"941","article-title":"Purpura fulminans due to Staphylococcus aureus.","volume-title":"Clin. Infect. Dis.","year":"2005"},{"key":"2026012806233338300_R11","first-page":"1123","article-title":"Four pediatric deaths from community-acquired methicillin-resistant Staphylococcus aureus, Minnesota and North Dakota, 1997\u20131999.","volume-title":"J. Am. Med. Assoc.","year":"1999"},{"key":"2026012806233338300_R12","first-page":"13","article-title":"Severe invasive group A streptococcal disease: clinical description and mechanisms of pathogenesis.","volume-title":"J. Lab. Clin. Med.","year":"1996"},{"key":"2026012806233338300_R13","first-page":"313","article-title":"Erythrogenic toxins A, B and C: occurrence of the genes and exotoxin formation from clinical Streptococcus pyogenes strains associated with streptococcal toxic shock-like syndrome.","volume-title":"FEMS Microb. Lett.","year":"1992"},{"key":"2026012806233338300_R14","first-page":"1562","article-title":"Molecular analysis of pyrogenic exotoxins from Streptococcus pyogenes isolates associated with toxic shock-like syndrome.","volume-title":"J. Clin. Microbiol.","year":"1991"},{"key":"2026012806233338300_R15","first-page":"2668","article-title":"Streptococcus pyogenes causing toxic-shock-like syndrome and other invasive diseases: clonal diversity and pyrogenic exotoxin expression.","volume-title":"Proc. Natl. Acad. Sci. USA","year":"1991"},{"key":"2026012806233338300_R16","first-page":"1890","article-title":"Quantification and toxicity of group A streptococcal pyrogenic exotoxins in an animal model of toxic shock syndrome-like illness.","volume-title":"J. Clin. Microbiol.","year":"1989"},{"key":"2026012806233338300_R17","first-page":"3369","article-title":"Association of phenotypic and genotypic characteristics of invasive Streptococcus pyogenes isolates with clinical components of streptococcal toxic shock syndrome.","volume-title":"Infect. Immun.","year":"1993"},{"key":"2026012806233338300_R18","first-page":"324","article-title":"Monkey feeding test for staphylococcal enterotoxin.","volume-title":"Methods Enzymol.","year":"1988"},{"key":"2026012806233338300_R19","first-page":"1149","article-title":"Staphylococcal enterotoxin B and toxic-shock syndrome toxin-1 are significantly associated with non-menstrual TSS.","volume-title":"Lancet","year":"1986"},{"key":"2026012806233338300_R20","first-page":"2875","article-title":"Reemergence of staphylococcal toxic shock syndrome in Minneapolis-St. Paul, Minnesota, during the 2000\u20132003 surveillance period.","volume-title":"J. Clin. Microbiol.","year":"2004"},{"key":"2026012806233338300_R21","first-page":"1017","article-title":"A new staphylococcal enterotoxin, enterotoxin F, associated with toxic-shock-syndrome Staphylococcus aureus isolates.","volume-title":"Lancet","year":"1981"},{"key":"2026012806233338300_R22","first-page":"509","article-title":"Identification and characterization of an exotoxin from Staphylococcus aureus associated with toxic-shock syndrome.","volume-title":"J. Infect. Dis.","year":"1981"},{"key":"2026012806233338300_R23","first-page":"1066","article-title":"The staphylococcal enterotoxins and their relatives.","volume-title":"Science","year":"1990"},{"key":"2026012806233338300_R24","first-page":"981","article-title":"Selective expansion of T cells expressing V\u03b22 in toxic shock syndrome.","volume-title":"J. Exp. Med.","year":"1990"},{"key":"2026012806233338300_R25"},{"key":"2026012806233338300_R26","first-page":"2583","article-title":"Staphylococcal enterotoxin B and toxic shock syndrome toxin-1 bind to distinct sites on HLA-DR and HLA-DQ molecules.","volume-title":"J. Immunol.","year":"1989"},{"key":"2026012806233338300_R27","first-page":"27","article-title":"The V\u03b2-specific superantigen staphylococcal enterotoxin B: stimulation of mature T cells and clonal deletion in neonatal mice.","volume-title":"Cell","year":"1989"},{"key":"2026012806233338300_R28","first-page":"2473","article-title":"Stimulation of B10.BR T cells with superantigenic staphylococcal toxins.","volume-title":"J. Immunol.","year":"1990"},{"key":"2026012806233338300_R29","first-page":"472","article-title":"Effect of antipyretics on group A streptococcal pyrogenic exotoxin fever production and ability to enhance lethal endotoxin shock.","volume-title":"Proc. Soc. Exp. Biol. Med.","year":"1978"},{"key":"2026012806233338300_R30","first-page":"167","article-title":"Comparisons of mouse and rabbit models of toxic shock syndrome.","volume-title":"Int. Congr. Symp. Ser.","year":"1998"},{"key":"2026012806233338300_R31","first-page":"7169","article-title":"Comparative analysis of lipopolysaccharide-induced tumor necrosis factor \u03b1 activity in serum and lethality in mice and rabbits pretreated with the staphylococcal superantigen toxic shock syndrome toxin 1.","volume-title":"Infect. Immun.","year":"2001"},{"key":"2026012806233338300_R32","first-page":"269","article-title":"Biogenic amine involvement in pyrogenicity and enhancement of lethal endotoxin shock by group A streptococcal pyrogenic exotoxin.","volume-title":"Proc. Soc. Exp. Biol. Med.","year":"1979"},{"key":"2026012806233338300_R33","first-page":"99","article-title":"Superantigens and their potential role in human disease.","volume-title":"Adv. Immunol.","year":"1993"},{"key":"2026012806233338300_R34","first-page":"9","article-title":"Porcine vagina ex vivo as a model for studying permeability and pathogenesis in mucosa.","volume-title":"J. Pharm. Sci.","year":"2008"},{"key":"2026012806233338300_R35","first-page":"25","article-title":"Streptococcal superantigens: streptococcal toxic shock syndrome. M. W. Cunningham, and R. S. Fujinami, eds.","volume-title":"Effects of Microbes on the Immune System","year":"2000"},{"key":"2026012806233338300_R36","first-page":"3630","article-title":"Pyrogenic toxin superantigen site specificity in toxic shock syndrome and food poisoning in animals.","volume-title":"Infect. Immun.","year":"2000"},{"key":"2026012806233338300_R37","first-page":"901","article-title":"Influence of the normal menstrual cycle on vaginal tissue, discharge, and microflora.","volume-title":"Clin. Infect. Dis.","year":"2000"},{"key":"2026012806233338300_R38","first-page":"1085","article-title":"Regional variation in content, composition and organization of porcine epithelial barrier lipids revealed by thin-layer chromatography and transmission electron microscopy.","volume-title":"Arch. Oral Biol.","year":"1995"},{"key":"2026012806233338300_R39","first-page":"967","article-title":"Epithelial cell layer thickness and immune cell populations in the normal human vagina at different stages of the menstrual cycle.","volume-title":"Am. J. Obstet. Gynecol.","year":"2000"},{"key":"2026012806233338300_R40","first-page":"7","article-title":"Biology of oral mucosa and esophagus.","volume-title":"J. Natl. Cancer Inst. Monogr.","year":"2001"},{"key":"2026012806233338300_R41","first-page":"571","article-title":"Comparative permeability of human vaginal and buccal mucosa to water.","volume-title":"Eur. J. Oral Sci.","year":"1997"},{"key":"2026012806233338300_R42","first-page":"85","article-title":"The physical, chemical and functional properties of lipids in the skin and other biological barriers.","volume-title":"Chem. Phys. Lipids","year":"1998"},{"key":"2026012806233338300_R43","first-page":"1091","article-title":"A comparative light-microscopic, electron-microscopic and chemical study of human vaginal and buccal epithelium.","volume-title":"Arch. Oral Biol.","year":"2001"},{"key":"2026012806233338300_R44","first-page":"1785","article-title":"Penetration of toxic shock syndrome toxin-1 across porcine vaginal mucosa ex vivo: permeability characteristics, toxin distribution, and tissue damage.","volume-title":"Am. J. Obstet. Gynecol.","year":"2003"},{"key":"2026012806233338300_R45","first-page":"2164","article-title":"The innate immune system is activated by stimulation of vaginal epithelial cells with Staphylococcus aureus and toxic shock syndrome toxin 1.","volume-title":"Infect. Immun.","year":"2005"},{"key":"2026012806233338300_R46","first-page":"1681","article-title":"The family of thiol-activated, cholesterol-binding cytolysins.","volume-title":"Toxicon","year":"2001"},{"key":"2026012806233338300_R47","first-page":"52","article-title":"Mechanism of membrane damage by streptolysin-O.","volume-title":"Infect. Immun.","year":"1985"},{"key":"2026012806233338300_R48","first-page":"281","article-title":"Cholesterol and the activity of bacterial toxins.","volume-title":"FEMS Microb. Lett.","year":"2004"},{"key":"2026012806233338300_R49","first-page":"1859","article-title":"Structure of staphylococcal \u03b1-hemolysin, a heptameric transmembrane pore.","volume-title":"Science","year":"1996"},{"key":"2026012806233338300_R50","first-page":"2630","article-title":"Subcytocidal attack by staphylococcal \u03b1 toxin activates NF-\u03baB and induces interleukin-8 production.","volume-title":"Infect. Immun.","year":"2001"},{"key":"2026012806233338300_R51","first-page":"337","article-title":"Streptolysin O and adherence synergistically modulate proinflammatory responses of keratinocytes to group A streptococci.","volume-title":"Mol. Microbiol.","year":"1998"},{"key":"2026012806233338300_R52","first-page":"237","article-title":"Resealing of large transmembrane pores produced by streptolysin O in nucleated cells is accompanied by NF-\u03baB activation and downstream events.","volume-title":"FASEB J.","year":"2002"},{"key":"2026012806233338300_R53","first-page":"S282","article-title":"Reaction of toxic shock syndrome toxin 1 with endothelium of human umbilical cord vein.","volume-title":"Rev Infect. Dis.","year":"1989"},{"key":"2026012806233338300_R54","first-page":"535","article-title":"Study of staphylococcal toxic shock syndrome toxin in human epithelial cell culture.","volume-title":"J. Infect. Dis.","year":"1984"},{"key":"2026012806233338300_R55","first-page":"566","article-title":"Staphylococcal toxic shock toxin specifically binds to cultured human epithelial cells and is rapidly internalized.","volume-title":"Infect. Immun.","year":"1984"},{"key":"2026012806233338300_R56","first-page":"711","article-title":"Effects of staphylococcal toxic shock syndrome toxin 1 on aortic endothelial cells.","volume-title":"J. Infect. Dis.","year":"1991"},{"key":"2026012806233338300_R57","first-page":"120","article-title":"Induction of tumor necrosis factor \u03b1 and interleukin-8 gene expression in bronchial epithelial cells by toxic shock syndrome toxin 1.","volume-title":"Infect. Immun.","year":"2000"},{"key":"2026012806233338300_R58","first-page":"120","article-title":"Active ion secretion and permeability of rabbit maxillary sinus epithelium, impact of staphylococcal enterotoxin B.","volume-title":"Otolaryngol Head Neck Surg.","year":"2000"},{"key":"2026012806233338300_R59","first-page":"115","article-title":"Staphylococcus aureus enterotoxins induce IL-8 secretion by human nasal epithelial cells.","volume-title":"Respir. Res.","year":"2006"},{"key":"2026012806233338300_R60","first-page":"1021","article-title":"Airway exposure to bacterial superantigen (SEB) induces lymphocyte-dependent airway inflammation associated with increased airway responsiveness: a model for non-allergic asthma.","volume-title":"Eur. J. Immunol.","year":"1999"},{"key":"2026012806233338300_R61","first-page":"6016","article-title":"Acute systemic immune activation following conjunctival exposure to staphylococcal enterotoxin B.","volume-title":"Infect. Immun.","year":"2006"},{"key":"2026012806233338300_R62","first-page":"51","article-title":"Acute systemic immune activation following vaginal exposure to staphylococcal enterotoxin B: implications for menstrual shock.","volume-title":"J. Reprod. Immunol.","year":"2007"},{"key":"2026012806233338300_R63","first-page":"647","article-title":"Intranasal exposure to staphylococcal enterotoxin B elicits an acute systemic inflammatory response.","volume-title":"Shock","year":"2006"},{"key":"2026012806233338300_R64","first-page":"1284","article-title":"Intranasal exposure to bacterial superantigens induces airway inflammation in HLA class II transgenic mice.","volume-title":"Infect. Immun.","year":"2006"},{"key":"2026012806233338300_R65","first-page":"123","article-title":"Enhancement of host susceptibility to lethal endotoxin shock by staphylococcal pyrogenic exotoxin type C.","volume-title":"Infect. Immun.","year":"1982"},{"key":"2026012806233338300_R66","first-page":"267","article-title":"Exotoxins of group A streptococci","volume-title":"Handbook of Natural Toxins: Bacterial Toxins","year":"1988"},{"key":"2026012806233338300_R67","first-page":"84","article-title":"Cloning and expression of streptococcal pyrogenic exotoxin A and staphylococcal toxic shock syndrome toxin-1 in Bacillus subtilis.","volume-title":"Mol. Gen. Genet.","year":"1987"},{"key":"2026012806233338300_R68","first-page":"160","article-title":"Evidence for two molecular forms of streptococcal erythrogenic toxin: conversion to a single form by 2-mercaptoethanol.","volume-title":"Eur. J. Biochem.","year":"1969"},{"key":"2026012806233338300_R69","first-page":"339","article-title":"Immunochemical assays for toxic shock syndrome toxin-1.","volume-title":"Methods Enzymol.","year":"1988"},{"key":"2026012806233338300_R70","first-page":"733","article-title":"\u03b1 toxin of Staphylococcus aureus.","volume-title":"Microbiol. Rev.","year":"1991"},{"key":"2026012806233338300_R71","first-page":"2125","article-title":"The E6 and E7 genes of human papillomavirus type 6 have weak immortalizing activity in human epithelial cells.","volume-title":"J. Virol.","year":"1992"},{"key":"2026012806233338300_R72","first-page":"84","article-title":"Both Rb\/p16INK4a inactivation and telomerase activity are required to immortalize human epithelial cells.","volume-title":"Nature","year":"1998"},{"key":"2026012806233338300_R73","first-page":"1994","article-title":"Superantigen-based immunotherapy: a phase I trial of PNU-214565, a monoclonal antibody-staphylococcal enterotoxin A recombinant fusion protein, in advanced pancreatic and colorectal cancer.","volume-title":"J. Clin. Oncol.","year":"1997"},{"key":"2026012806233338300_R74","first-page":"516","article-title":"Molecular identification of a danger signal that alerts the immune system to dying cells.","volume-title":"Nature","year":"2003"},{"key":"2026012806233338300_R75","first-page":"1058","article-title":"Successful management of a serious group A streptococcal infection during the third trimester of pregnancy.","volume-title":"Clin. Infect. Dis.","year":"1995"},{"key":"2026012806233338300_R76","first-page":"1557","article-title":"Oral mucosal permeability and stability of transforming growth factor \u03b2-3 in vitro.","volume-title":"Pharm. Res.","year":"1999"},{"key":"2026012806233338300_R77","first-page":"211","article-title":"The systemic reaction during inflammation: the acute-phase proteins.","volume-title":"Protein Pept. Lett.","year":"2002"},{"key":"2026012806233338300_R78","first-page":"409","article-title":"The CC chemokine CCL20 and its receptor CCR6.","volume-title":"Cytokine Growth Factor Rev.","year":"2003"},{"key":"2026012806233338300_R79","first-page":"970","article-title":"Orchestrating the orchestrators: chemokines in control of T cell traffic.","volume-title":"Nat. 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