Abstract

Staphylococcus aureus causes significant illnesses throughout the world, including toxic shock syndrome (TSS), pneumonia, and infective endocarditis. Major contributors to S. aureus illnesses are secreted virulence factors it produces, including superantigens and cytolysins. This study investigates the use of superantigens and cytolysins as staphylococcal vaccine candidates. Importantly, 20% of humans and 50% of rabbits in our TSS model cannot generate antibody responses to native superantigens. We generated three TSST-1 mutants; G31S/S32P, H135A, and Q136A. All rabbits administered these TSST-1 toxoids generated strong antibody responses (titers>10,000) that neutralized native TSST-1 in TSS models, both in vitro and in vivo. These TSST-1 mutants lacked detectable residual toxicity. Additionally, the TSST-1 mutants exhibited intrinsic adjuvant activity, increasing antibody responses to a second staphylococcal antigen (β-toxin). This effect may be due to TSST-1 mutants binding to the immune co-stimulatory molecule CD40. The superantigens TSST-1 and SEC and the cytolysin α-toxin are known to contribute to staphylococcal pneumonia. Immunization of rabbits against these secreted toxins provided complete protection from highly lethal challenge with a USA200 S. aureus strain producing all three exotoxins; USA200 strains are common causes of staphylococcal infections. The same three exotoxins plus the cytolysins β-toxin and γ-toxin contribute to infective endocarditis and sepsis caused by USA200 strains. Immunization against these five exotoxins protected rabbits from infective endocarditis and lethal sepsis. These data suggest that immunization against toxoid proteins of S. aureus exotoxins protects from serious illnesses, and concurrently superantigen toxoid mutants provide endogenous adjuvant activity.

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Publisher Full Text

Authors

Spaulding AR, Lin YC, Merriman JA, Brosnahan AJ, Peterson ML, Schlievert PM

Institution

Department of Microbiology, Medical School, University of Minnesota, Minneapolis, MN 55455, USA. adam-spaulding@uiowa.edu

Source

Vaccine 30:34 2012 Jul 20 pg 5099-109

MeSH

Adjuvants, Immunologic
Animals
Antibodies, Bacterial
Antibody Formation
Antigens, CD40
Bacterial Proteins
Bacterial Toxins
Cell Line
Cytotoxins
Endocarditis, Bacterial
Exotoxins
Female
Hemolysin Proteins
Humans
Male
Neutralization Tests
Pneumonia, Staphylococcal
Rabbits
Shock, Septic
Staphylococcal Infections
Staphylococcal Toxoid
Staphylococcal Vaccines
Staphylococcus aureus
Superantigens
Vaccination

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

22691432