Staphylococcal Superantigens Stimulate Epithelial Cells through CD40 To Produce Chemokines

ABSTRACT Mucosal and skin tissues form barriers to infection by most bacterial pathogens. Staphylococcus aureus causes diseases across these barriers in part dependent on the proinflammatory properties of superantigens. We showed, through use of a CRISPR-Cas9 CD40 knockout, that the superantigens to...

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Autores principales:	Patrick M. Schlievert, Michael P. Cahill, Bruce S. Hostager, Amanda J. Brosnahan, Aloysius J. Klingelhutz, Francoise A. Gourronc, Gail A. Bishop, Donald Y. M. Leung
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	CD40 Staphylococcus aureus chemokines superantigens toxic shock syndrome toxin Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/49782844522c4c8c856aa6a48efa7298
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spelling	oai:doaj.org-article:49782844522c4c8c856aa6a48efa72982021-11-15T15:55:24ZStaphylococcal Superantigens Stimulate Epithelial Cells through CD40 To Produce Chemokines10.1128/mBio.00214-192150-7511https://doaj.org/article/49782844522c4c8c856aa6a48efa72982019-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00214-19https://doaj.org/toc/2150-7511ABSTRACT Mucosal and skin tissues form barriers to infection by most bacterial pathogens. Staphylococcus aureus causes diseases across these barriers in part dependent on the proinflammatory properties of superantigens. We showed, through use of a CRISPR-Cas9 CD40 knockout, that the superantigens toxic shock syndrome toxin 1 (TSST-1) and staphylococcal enterotoxins (SEs) B and C stimulated chemokine production from human vaginal epithelial cells (HVECs) through human CD40. This response was enhanced by addition of antibodies against CD40 through an unknown mechanism. TSST-1 was better able to stimulate chemokine (IL-8 and MIP-3α) production by HVECs than SEB and SEC, suggesting this is the reason for TSST-1’s exclusive association with menstrual TSS. A mutant of TSST-1, K121A, caused TSS in a rabbit model when administered vaginally but not intravenously, emphasizing the importance of the local vaginal environment. Collectively, our data suggested that superantigens facilitate infections by disruption of mucosal barriers through their binding to CD40, with subsequent expression of chemokines. The chemokines facilitate TSS and possibly other epithelial conditions after attraction of the adaptive immune system to the local environment. IMPORTANCE Menstrual toxic shock syndrome (TSS) is a serious infectious disease associated with vaginal colonization by Staphylococcus aureus producing the exotoxin TSS toxin 1 (TSST-1). We show that menstrual TSS occurs after TSST-1 interaction with an immune costimulatory molecule called CD40 on the surface of vaginal epithelial cells. Other related toxins, where the entire family is called the superantigen family, bind to CD40, but not with a high-enough apparent affinity to cause TSS; thus, TSST-1 is the only exotoxin superantigen associated. Once the epithelial cells become activated by TSST-1, they produce soluble molecules referred to as chemokines, which in turn facilitate TSST-1 activation of T lymphocytes and macrophages to cause the symptoms of TSS. Identification of small-molecule inhibitors of the interaction of TSST-1 with CD40 may be useful so that they may serve as additives to medical devices, such as tampons and menstrual cups, to reduce the incidence of menstrual TSS.Patrick M. SchlievertMichael P. CahillBruce S. HostagerAmanda J. BrosnahanAloysius J. KlingelhutzFrancoise A. GourroncGail A. BishopDonald Y. M. LeungAmerican Society for MicrobiologyarticleCD40Staphylococcus aureuschemokinessuperantigenstoxic shock syndrome toxinMicrobiologyQR1-502ENmBio, Vol 10, Iss 2 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	CD40 Staphylococcus aureus chemokines superantigens toxic shock syndrome toxin Microbiology QR1-502
spellingShingle	CD40 Staphylococcus aureus chemokines superantigens toxic shock syndrome toxin Microbiology QR1-502 Patrick M. Schlievert Michael P. Cahill Bruce S. Hostager Amanda J. Brosnahan Aloysius J. Klingelhutz Francoise A. Gourronc Gail A. Bishop Donald Y. M. Leung Staphylococcal Superantigens Stimulate Epithelial Cells through CD40 To Produce Chemokines
description	ABSTRACT Mucosal and skin tissues form barriers to infection by most bacterial pathogens. Staphylococcus aureus causes diseases across these barriers in part dependent on the proinflammatory properties of superantigens. We showed, through use of a CRISPR-Cas9 CD40 knockout, that the superantigens toxic shock syndrome toxin 1 (TSST-1) and staphylococcal enterotoxins (SEs) B and C stimulated chemokine production from human vaginal epithelial cells (HVECs) through human CD40. This response was enhanced by addition of antibodies against CD40 through an unknown mechanism. TSST-1 was better able to stimulate chemokine (IL-8 and MIP-3α) production by HVECs than SEB and SEC, suggesting this is the reason for TSST-1’s exclusive association with menstrual TSS. A mutant of TSST-1, K121A, caused TSS in a rabbit model when administered vaginally but not intravenously, emphasizing the importance of the local vaginal environment. Collectively, our data suggested that superantigens facilitate infections by disruption of mucosal barriers through their binding to CD40, with subsequent expression of chemokines. The chemokines facilitate TSS and possibly other epithelial conditions after attraction of the adaptive immune system to the local environment. IMPORTANCE Menstrual toxic shock syndrome (TSS) is a serious infectious disease associated with vaginal colonization by Staphylococcus aureus producing the exotoxin TSS toxin 1 (TSST-1). We show that menstrual TSS occurs after TSST-1 interaction with an immune costimulatory molecule called CD40 on the surface of vaginal epithelial cells. Other related toxins, where the entire family is called the superantigen family, bind to CD40, but not with a high-enough apparent affinity to cause TSS; thus, TSST-1 is the only exotoxin superantigen associated. Once the epithelial cells become activated by TSST-1, they produce soluble molecules referred to as chemokines, which in turn facilitate TSST-1 activation of T lymphocytes and macrophages to cause the symptoms of TSS. Identification of small-molecule inhibitors of the interaction of TSST-1 with CD40 may be useful so that they may serve as additives to medical devices, such as tampons and menstrual cups, to reduce the incidence of menstrual TSS.
format	article
author	Patrick M. Schlievert Michael P. Cahill Bruce S. Hostager Amanda J. Brosnahan Aloysius J. Klingelhutz Francoise A. Gourronc Gail A. Bishop Donald Y. M. Leung
author_facet	Patrick M. Schlievert Michael P. Cahill Bruce S. Hostager Amanda J. Brosnahan Aloysius J. Klingelhutz Francoise A. Gourronc Gail A. Bishop Donald Y. M. Leung
author_sort	Patrick M. Schlievert
title	Staphylococcal Superantigens Stimulate Epithelial Cells through CD40 To Produce Chemokines
title_short	Staphylococcal Superantigens Stimulate Epithelial Cells through CD40 To Produce Chemokines
title_full	Staphylococcal Superantigens Stimulate Epithelial Cells through CD40 To Produce Chemokines
title_fullStr	Staphylococcal Superantigens Stimulate Epithelial Cells through CD40 To Produce Chemokines
title_full_unstemmed	Staphylococcal Superantigens Stimulate Epithelial Cells through CD40 To Produce Chemokines
title_sort	staphylococcal superantigens stimulate epithelial cells through cd40 to produce chemokines
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/49782844522c4c8c856aa6a48efa7298
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Staphylococcal Superantigens Stimulate Epithelial Cells through CD40 To Produce Chemokines

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