Novel toxic shock syndrome toxin-1 amino acids required for biological activity

Amanda J Brosnahan; Matthew M Schaefers; William H Amundson; Mary J Mantz; Christopher A Squier; Marnie L Peterson; Patrick M Schlievert

doi:10.1021/bi801468w

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Novel toxic shock syndrome toxin-1 amino acids required for biological activity

Journal article

Peer reviewed

Novel toxic shock syndrome toxin-1 amino acids required for biological activity

Amanda J Brosnahan, Matthew M Schaefers, William H Amundson, Mary J Mantz, Christopher A Squier, Marnie L Peterson and Patrick M Schlievert

Biochemistry (Easton), Vol.47(49), pp.12995-13003

12/09/2008

DOI: 10.1021/bi801468w

PMCID: PMC2645936

PMID: 19012411

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Abstract

Superantigens interact with T lymphocytes and macrophages to cause T lymphocyte proliferation and overwhelming cytokine production, which lead to toxic shock syndrome. Staphylococcus aureus superantigen toxic shock syndrome toxin-1 is a major cause of menstrual toxic shock syndrome. In general, superantigen-secreting S. aureus remains localized at the vaginal surface, and the superantigen must therefore penetrate the vaginal mucosa to interact with underlying immune cells to cause toxic shock syndrome. A dodecapeptide region (toxic shock syndrome toxin-1 amino acids F119-D130), relatively conserved among superantigens, has been implicated in superantigen penetration of the epithelium. The purpose of this study was to determine amino acids within this dodecapeptide region that are required for interaction with vaginal epithelium. Alanine mutations were constructed in S. aureus toxic shock syndrome toxin-1 amino acids D120 to D130. All mutants maintained superantigenicity, and selected mutants were lethal when given intravenously to rabbits. Toxic shock syndrome toxin-1 induces interleukin-8 from immortalized human vaginal epithelial cells; however, three toxin mutants (S127A, T128A, and D130A) induced low levels of interleukin-8 compared to wild type toxin. When carboxy-terminal mutants (S127A to D130A) were administered vaginally to rabbits, D130A was nonlethal, while S127A and T128A demonstrated delayed lethality compared to wild type toxin. In a porcine ex vivo permeability model, mutant D130A penetrated the vaginal mucosa more quickly than wild type toxin. Toxic shock syndrome toxin-1 residue D130 may contribute to binding an epithelial receptor, which allows it to penetrate the vaginal mucosa, induce interleukin-8, and cause toxic shock syndrome.

Mutation

Superantigens - toxicity

Epithelial Cells - metabolism

Injections, Intravenous

Enterotoxins - toxicity

Culture Techniques

Peptides - genetics

Vagina - immunology

Bacterial Toxins - toxicity

Cell Membrane Permeability

Amino Acids - genetics

Peptides - toxicity

Alanine - genetics

Swine

Base Sequence

Female

Interleukin-8 - metabolism

Binding Sites

Rabbits

Alanine - toxicity

Peptides - chemistry

Lymphocyte Activation

Amino Acids - analysis

Shock, Septic - physiopathology

Bacterial Toxins - chemistry

Amino Acids - toxicity

Animals

Superantigens - chemistry

Epithelial Cells - immunology

Vagina - metabolism

Enterotoxins - chemistry

Interleukin-8 - immunology

Alanine - analysis

Details

Title: Subtitle: Novel toxic shock syndrome toxin-1 amino acids required for biological activity
Creators: Amanda J Brosnahan - Department of Microbiology, University of Minnesota Medical School, 420 Delaware Street SE, Minneapolis, Minnesota 55455, USA
Matthew M Schaefers
William H Amundson
Mary J Mantz
Christopher A Squier
Marnie L Peterson
Patrick M Schlievert
Resource Type: Journal article
Publication Details: Biochemistry (Easton), Vol.47(49), pp.12995-13003
DOI: 10.1021/bi801468w
PMID: 19012411
PMCID: PMC2645936
NLM abbreviation: Biochemistry
ISSN: 0006-2960
eISSN: 1520-4995
Publisher: United States
Grant note: R01 AI074283 / NIAID NIH HHS AI074283 / NIAID NIH HHS R01 AI074283-20 / NIAID NIH HHS
Language: English
Date published: 12/09/2008
Academic Unit: Oral Pathology, Radiology and Medicine; Microbiology and Immunology; International Programs; Internal Medicine
Record Identifier: 9984001136002771

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