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Penetration of Stratified Mucosa Cytolysins Augment Superantigen Cytolysins Augment Superantigen Penetration of Stratified Mucosa Amanda J. Brosnahan, Mary J. Mantz, Christopher A. Squier, Marnie L. Peterson and Patrick M. Schlievert This information is current as of September 25, 2021. J Immunol 2009; 182:2364-2373; ; doi: 10.4049/jimmunol.0803283 http://www.jimmunol.org/content/182/4/2364 Downloaded from References This article cites 76 articles, 24 of which you can access for free at: http://www.jimmunol.org/content/182/4/2364.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 25, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2009 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Cytolysins Augment Superantigen Penetration of Stratified Mucosa1 Amanda J. Brosnahan,* Mary J. Mantz,† Christopher A. Squier,† Marnie L. Peterson,‡ and Patrick M. Schlievert2* 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 ␣-toxin and the streptococcal cytolysin strep- tolysin O enhanced penetration of toxic shock syndrome toxin-1 and streptococcal pyrogenic exotoxin A, respectively, across Downloaded from 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 dem- onstrated that although both superantigens were proinflammatory, only the staphylococcal cytolysin ␣-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␤. Two separate models of superantigen penetration are proposed: staphylococcal ␣-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 http://www.jimmunol.org/ streptolysin O directly damages the mucosa to allow for penetration of streptococcal pyrogenic exotoxin A and possibly viable streptococci. The Journal of Immunology, 2009, 182: 2364–2373. uperantigens produced by the Gram-positive pathogens their unique mechanism of T cell stimulation (23). These exotoxins Streptococcus pyogenes and Staphylococcus aureus are bind to the variable region of the ␤-chain of the TCR (V␤-TCR) the major factors in a variety of severe infections such as and MHC II on APCs such as macrophages (24–28). This inter- S 3 toxic shock syndrome (TSS) (1–7), scarlet fever (8), necrotizing action leads to the proliferation and activation of a large number of fasciitis (9), purpura fulminans (10), and necrotizing pneumonia T cells and the release of cytokines from both cell types. The by guest on September 25, 2021 (11). Superantigens made by Str. pyogenes include the streptococ- production of TNF-␣ and -␤ results in capillary leakage, IL-1␤ cal pyrogenic exotoxins (SPE) A, C, G, H, I, J, K, L, and M, (IL-1␤) causes fever, and IL-2 and IFN-␥ cause rash (8, 29–33). streptococcal superantigen, and streptococcal mitogenic exotoxin The effects of the massive cytokine release caused by superanti- Z. SPE A and SPE C have been implicated in most cases of strep- gens will eventually lead to hypotension, shock, and if not treated tococcal TSS (12–17). Of the superantigens made by Sta. aureus, properly, death. the staphylococcal enterotoxins B (SEB) and C are responsible for Much is known about the interaction of superantigens with im- half of the cases of nonmenstrual TSS, whereas the other half are mune cells systemically, but their role at the mucosal surface is caused by TSS toxin-1 (TSST-1) (18–22). TSST-1 is also respon- unknown. Both Str. pyogenes and Sta. aureus typically colonize sible for the majority of menstrual TSS (mTSS) cases. Superanti- nonkeratinized stratified squamous epithelia to initiate infections, gens were aptly named by Marrack and Kappler in 1990 due to with Str. pyogenes initiating severe infections often following oral mucosal colonization and mTSS initiating from vaginal mucosa (34, 35); an important difference in streptococcal TSS and staph- *Department of Microbiology, University of Minnesota Medical School, Minneapo- lis, MN 55455; †Dows Institute for Dental Research, College of Dentistry, University ylococcal mTSS is that streptococci typically invade systemically, of Iowa, Iowa City, IA 52246, and ‡Department of Experimental and Clinical Phar- whereas Sta. aureus remains on the mucosal surface (3, 4, 35). macology, University of Minnesota College of Pharmacy, Minneapolis, MN 55455 Subsequent to initial bacterial colonization, superantigens may in- Received for publication October 1, 2008. Accepted for publication November teract with the mucosa in at least two ways: 1) superantigens may 30, 2008. penetrate through the mucosa to reach adaptive immune cells lo- The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance cated in the underlying tissues; and 2) superantigens may exert with 18 U.S.C. Section 1734 solely to indicate this fact. effects directly on epithelial cells that contribute to the course of 1 This research was supported by U.S. Public Health Service Research Grant the infection. In fact, TSST-1 is known to penetrate the vaginal AI074283 and funding from the Minnesota Medical Foundation. mucosa to cause mTSS even as Sta. aureus remains localized at the 2 Address correspondence and reprint requests to Dr. Patrick M. Schlievert, Depart- vaginal surface (3, 4). It has been shown that there are differences ment of Microbiology, University of Minnesota Medical School, 420 Delaware Street Southeast, Minneapolis, MN 55455 among the superantigens in their ability to penetrate mucosal sur- faces to cause TSS and lethality in a rabbit model (36). When 3 Abbreviations used in this paper: TSS, toxic shock syndrome; HVEC, human vag- inal epithelial cell; IEF, isoelectric focusing; mTSS, menstrual TSS; SEB, staphylo- administered vaginally to rabbits, TSST-1 is the most lethal, fol- coccal enterotoxin B; SLO, streptolysin O; SPE, streptococcal pyrogenic exotoxin; lowed by SEC1 (staphylococcal enterotoxin C1) and then SPE A, TSST-1, TSS toxin-1. whereas all three superantigens are lethal when administered i.v Copyright © 2009 by The American Association of Immunologists, Inc. 0022-1767/09/$2.00 (36). High doses of TSST-1 are also lethal when administered www.jimmunol.org/cgi/doi/10.4049/jimmunol.0803283 The Journal of Immunology 2365 orally; thus TSST-1 appears to penetrate mucosal surfaces better matory cytokine production from human vaginal epithelial cells than other superantigens (36). (HVECs) (45). The second objective of the present study was to eval- Porcine vagina ex vivo has also been used to analyze the ability uate the ability of superantigens (TSST-1 and SPE A) and cytolysins of TSST-1 to penetrate the mucosa. Ex vivo porcine tissue is an (␣-toxin and SLO) to induce cytokine responses from HVECs. excellent model of human vaginal tissue; vaginal tissue from both In the present study we show that ␣-toxin and SLO act to en- human and pig is a nonkeratinized stratified squamous epithelium hance penetration of TSST-1 and SPE A, respectively, across ex with intercellular lipids, including ceramides, glucosyl ceramides, vivo porcine vaginal mucosa in a model of superantigen penetra- and cholesterol located in the surface layers (34, 37–43). As tight tion. Both cytolysins cause localized damage and inflammation in junctions are not present between the cells of the vaginal mucosa, the ex vivo porcine tissue; however purified cytolysins added to the intercellular lipids constitute a permeability barrier. TSST-1 HVECs induced cell damage and death to different extents. Supe- labeled with [35S]methionine has been shown to cross the ex vivo rantigens incubated with HVECs induce proinflammatory cytokine porcine vaginal mucosa with significant amounts of toxin remain- and chemokine responses from the cells, but these responses are ing within the tissue (44). Studies by Peterson et al. demonstrated altered when cytolysin is present. Based on these data, we propose
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