Role of a carboxy-terminal site of toxic shock syndrome toxin 1 in eliciting immune responses of human peripheral blood mononuclear cells.
Staphylococcus aureus toxic shock syndrome toxin 1 (TSST-1) is involved in the pathogenesis of toxic shock syndrome and perhaps other staphylococcal diseases. Recently, the C-terminal part of the TSST-1 toxin has been shown to be responsible for mitogenic activity in animal models. We studied the role of the C-terminal structural unit of TSST-1 with regard to proliferation, cytokine release (tumor necrosis factor alpha [TNF-alpha], interleukin-6 [IL-6], and IL-8), mRNA expression for IL-6, IL-8, IL-10, TNF-alpha, and CD40 ligand (CD40L), synthesis of immunoglobulin E (IgE), IgA, IgG, and IgM, CD23 expression, and soluble CD23 (sCD23) release from human peripheral blood mononuclear cells (PBMC). For this purpose, we used the recombinant wild-type TSST-1 (p17) mutant toxin Y115A (tyrosine residue modified to alanine) and toxin H135A (histidine residue modified to alanine). Unmodified toxin p17 and mutant toxin Y115A, at a concentration below 5 ng, to a lesser degree, induced a strong proliferation. Toxin p17 followed by toxin Y115A was the most pronounced inducer for mRNA expression for IL-10 and CD40L and cytokine generation (mRNA and protein) for TNF-alpha, IL-6, and IL-8. Mutant protein H135A failed to activate human PBMC. Both toxins p17 and, to a lesser degree, Y115A significantly suppressed IL-4- and anti-CD40-induced synthesis of all four Igs as well as IL-4-induced CD23 expression and sCD23 release. Mutant toxin H135A failed to do so. Thus, our data show that a region in the C terminus of TSST-1 is responsible not only for mitogenic activity but also for additional immunomodulating biological activities of TSST-1. More specifically, histidine residue H135A of the 194-amino-acid toxin appears to be critical for the expression of biological activities in a human in vitro model.
Drynda
A
A
Ruhr-Universität Bochum, Medizinische Mikrobiologie und Immunologie AG, Germany.
König
B
B
Bonventre
P F
PF
König
W
W
D015703:Antigens, CD / Q000235:genetics; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics; D001427:Bacterial Toxins; D001483:Base Sequence; D019013:CD40 Antigens; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D004768:Enterotoxins / Q000276:immunology*; D006801:Humans; D007132:Immunoglobulin Isotypes / Q000096:biosynthesis; D016753:Interleukin-10 / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000032:analysis; D017455:Receptors, IgE / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000276:immunology; D013211:Staphylococcus aureus / Q000276:immunology*; D013329:Structure-Activity Relationship; D018089:Superantigens / Q000276:immunology*
D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D001427:Bacterial Toxins; D019013:CD40 Antigens; D016207:Cytokines; D004768:Enterotoxins; D007132:Immunoglobulin Isotypes; D012333:RNA, Messenger; D017455:Receptors, IgE; D011994:Recombinant Proteins; D018089:Superantigens; C030107:enterotoxin F, Staphylococcal; D016753:Interleukin-10