title: Human leukocyte antigen-DQ8 transgenic mice: a model to examine the toxicity of aerosolized staphylococcal enterotoxin B.
abstract: 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.
authors.affiliation: U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD 21702, USA.
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Roy
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Warfield
authors.forename: Brent C
authors.initials: BC
authors.lastname: Welcher
authors.forename: Raoul F
authors.initials: RF
authors.lastname: Gonzales
authors.forename: Tom
authors.initials: T
authors.lastname: Larsen
authors.forename: Julie
authors.initials: J
authors.lastname: Hanson
authors.forename: Chella S
authors.initials: CS
authors.lastname: David
authors.forename: Theresa
authors.initials: T
authors.lastname: Krakauer
authors.forename: Sina
authors.initials: S
authors.lastname: Bavari
mesh_terms: 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
chemical_list: D000336:Aerosols; D016207:Cytokines; D004768:Enterotoxins; D006683:HLA-DQ Antigens; C109756:HLA-DQ8 antigen; C031818:enterotoxin B, staphylococcal