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.Staphylococcus aureus and group A streptococci are responsible for a wide range of mild to life-threatening infections, including scarlet fever, pharyngitis, dermatitis, infectious arthritis, and toxic shock syndrome (2, 13, 18, 25, 31). These pathogenic bacteria use several virulence mechanisms to enhance their toxicity after infection, including the M protein, diffusible enzymes (e.g., DNase), and streptolysin. Furthermore, many strains of S. aureus produce bacterial superantigens (BSAgs), which exert a series of critical, negative immunological effects on the host. Specifically, BSAgs bind to major histocompatibility complex (MHC) class II molecules and form a ternary complex with receptive variable ␤ chains of T-cell antigen receptors. After binding, BSAg-stimulated T cells are eliminated by a Fas/Fas-ligand-mediated apoptosis or, alternatively, enter a state of specific nonresponsiveness (anergy), which may last for several months. Furthermore, BSAgs may exacerbate subclinical viral infections by removing activated T cells from their normal role in clearing invasive organisms.Mice are naturally insensitive to BSAg-induced lethal shock (23,24,32). In order to overcome the natural insensitivity of mice to staphylococcal enterotoxins (SEs), sublethal amounts of lipopolysaccharide (LPS) have been used to potentiate the lethal effects of BSAgs (7,32). Although the exact mechanism of LPS induction is not known, it has been shown that lethality is dependent on the expression of mo...

Interference of the T Cell and Antigen-Presenting Cell Costimulatory Pathway Using CTLA4-Ig (Abatacept) Prevents Staphylococcal Enterotoxin B Pathology

“…SEB is more toxic via inhalation, compared with ingestion, and severe lung damage after exposure to SEB aerosols has been demonstrated (23). Numerous animal models of SEB intoxication have been developed that use survival as a primary outcome for the efficacy of medical countermeasures (24,25). However, weaponized SEB has potential incapacitating properties for exposed military personnel because of the ED 50 (the median effective dose of incapacitation) being ∼50 times lower than the LD 50 (26,27).…”

Human Leukocyte Antigen Class II Transgenic Mouse Model Unmasks the Significant Extrahepatic Pathology in Toxic Shock Syndrome

“…Challenging HLA-II transgenic mice with SAgs thorough several different routes elicits robust SIRS and renders them highly susceptible to TSS. [40][41][42][43][44][45][46][47][48][49] One of our HLA-II transgenic lines that expresses HLA-DR3 is extremely sensitive to SEB. HLA-DR3 transgenic mice readily die of SEB-induced TSS without D-galN sensitization.…”

HLA Transgenic Mice Provide Evidence for a Direct and Dominant Role of HLA Class II Variation in Modulating the Severity of Streptococcal Sepsis

“…This difference relates, in part, to the lower binding affinity of SAgs to murine MHC class II as compared with human HLA class II (21). The advent of the HLA class II transgenic (HLA-tg) mice provided an opportunity to study the pathogenesis of GAS in a readily manipulated animal model with a sensitivity to SAgs similar to that of humans (22)(23)(24)(25)(26). Indeed, several studies have shown that HLA-tg mice mount potent responses to GAS SAgs (20,23,25,27,28).…”