Human leukocyte antigen-DQ8 transgenic mice: a model to examine the toxicity of aerosolized staphylococcal enterotoxin B.
Staphylococcal enterotoxins (SEs) belong to a large group of bacterial exotoxins that cause severe immunopathologies, especially when delivered as an aerosol. SEs elicit the release of lethal amounts of cytokines by binding to major histocompatibility complex (MHC) class II and cross-linking susceptible T-cell receptors. Efforts to develop effective therapeutic strategies to protect against SEs delivered as an aerosol have been hampered by the lack of small animal models that consistently emulate human responses to these toxins. Here, we report that human leukocyte antigen-DQ8 (HLA-DQ8) transgenic (Tg) mice, but not littermate controls, succumbed to lethal shock induced by SEB aerosols without potentiation. Substantial amounts of perivascular edema and inflammatory infiltrates were noted in the lungs of Tg mice, similar to the pathology observed in nonhuman primates exposed by aerosol to SEB. Furthermore, the observed pathologies and lethal shock correlated with an upsurge in proinflammatory cytokine mRNA gene expression in the lungs and spleens, as well as with marked increases in the levels of proinflammatory circulating cytokines in the Tg mice. Unlike the case for littermate controls, telemetric evaluation showed significant hypothermia in Tg mice exposed to lethal doses of SEB. Taken together, these results show that this murine model will allow for the examination of therapeutics and vaccines developed specifically against SEB aerosol exposure and possibly other bacterial superantigens in the context of human MHC class II receptors.
Roy
Chad J
CJ
U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD 21702, USA.
Warfield
Kelly L
KL
Welcher
Brent C
BC
Gonzales
Raoul F
RF
Larsen
Tom
T
Hanson
Julie
J
David
Chella S
CS
Krakauer
Theresa
T
Bavari
Sina
S
D000336:Aerosols; D000818:Animals; D001831:Body Temperature; D016207:Cytokines / Q000096:biosynthesis; D004768:Enterotoxins / Q000633:toxicity*; D006683:HLA-DQ Antigens / Q000235:genetics / Q000502:physiology*; D008168:Lung / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
D000336:Aerosols; D016207:Cytokines; D004768:Enterotoxins; D006683:HLA-DQ Antigens; C109756:HLA-DQ8 antigen; C031818:enterotoxin B, staphylococcal