Lethal shock induced by streptococcal pyrogenic exotoxin A in mice transgenic for human leukocyte antigen-DQ8 and human CD4 receptors: implications for development of vaccines and therapeutics.
Streptococcal and staphylococcal infections result in significant human morbidity and mortality. This study used a transgenic murine model expressing human major histocompatibility complex (MHC) class II and human CD4 in which, without additional toxic sensitization, human-like responses to the bacterial superantigen (SAg) streptococcal pyrogenic exotoxin A (SpeA) could be simulated, as determined by studying multiple biologic effects of the SAgs in vivo. Expression of human leukocyte antigen (HLA)-DQ8 rendered the mice susceptible to SpeA-induced lethal shock that was accompanied by massive cytokine production and marked elevation of serum alanine and aspartate aminotransferase levels. Of importance, this model enabled examination of the efficacy of an engineered non-SAg vaccine candidate against SpeA in the context of HLA. This report is thought to be the first of a lethal shock triggered in mice by bacterial SAgs without prior sensitization and examination of a vaccine against streptococcal SAg in the context of human MHC receptors.
Department of Cell Biology and Biochemistry, US Army Medical Research Institute of Infectious Diseases, Frederick, Maryland, USA. bwelche@mail.nih.gov
Brent C
BC
Welcher
John H
JH
Carra
Luis
L
DaSilva
Juli
J
Hanson
Chella S
CS
David
M Javad
MJ
Aman
Sina
S
Bavari
D000818:Animals; D001426:Bacterial Proteins; D015704:CD4 Antigens / Q000235:genetics* / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D005098:Exotoxins / Q000235:genetics / Q000276:immunology / Q000633:toxicity*; D006683:HLA-DQ Antigens / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000201:enzymology; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism; D012772:Shock, Septic / Q000209:etiology* / Q000276:immunology / Q000401:mortality; D013290:Streptococcal Infections / Q000209:etiology / Q000517:prevention & control; D022541:Streptococcal Vaccines / Q000008:administration & dosage / Q000276:immunology; D013297:Streptococcus pyogenes / Q000276:immunology; D018089:Superantigens / Q000276:immunology / Q000633:toxicity*; D013601:T-Lymphocytes / Q000276:immunology; D019076:Transgenes
D001426:Bacterial Proteins; D015704:CD4 Antigens; D016207:Cytokines; D005098:Exotoxins; D006683:HLA-DQ Antigens; C109756:HLA-DQ8 antigen; D008565:Membrane Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; C117980:SpeA protein, Streptococcus pyogenes; D022541:Streptococcal Vaccines; D018089:Superantigens; C027951:erythrogenic toxin