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Kinetics of cellular and cytokine responses in a chimeric mouse model for the study of staphylococcal enterotoxin B
L Yuan1, G H Lowell, D L Hoover
1Department of Bacterial Diseases, Walter Reed Army Institute of Research, Washington, DC 20307-5100, USA.
Abstract:
The mechanisms by which superantigens, such as staphylococcal enterotoxin B (SEB), contribute to microbial pathogenicity have been poorly defined. The study of such pathogenic processes has been hampered by the lack of an adequate animal model. We utilized a previously described murine chimeric model to determine the cytokines and cell populations that might be involved in SEB toxicity. In the absence of bone marrow transplantation (BMT), all total body irradiated (TBI) mice died, while all transplanted mice survived up to 6 months. Compared with non-TBI and non-BMT mice, chimeric mice had an increased percentage of CD11b (Mac-1)-positive splenocytes (17 vs. 59%, P < 0.05) and decreased CD45R-positive (B) cells (33 vs. 6%, P < 0.05) at 6 weeks after BMT. The relative numbers of splenocyte CD4 and CD8 cells were similar in chimeric and normal mice. Susceptibility of chimeric animals to 10 or 100 microg SEB was time-dependent: no mice challenged at 2 weeks post-BMT died, but 15% of mice challenged at 4 weeks and 50% of those challenged at 6-8 weeks died. Compared with TBI and non-BMT C3H/HeJ mice, SEB-challenged chimeric mice at 6-8 weeks had (1) increased splenocyte mRNA expression for: IFN-gamma (3.5 x optimally at 1 h), TNF-alpha (6.5 x at 2 h), IL-6 (4.8 x at 4 h), IL-1beta (8.4 x at 4 h), IL-2 (4.7 x at 4 h), and IL-10 (3 x at 16 h), and (2) increased and earlier peak serum levels of IFN-gamma, IL-6, IL-1beta and IL-2, but no increase in serum TNF-alpha or IL-4. These data support the hypothesis that the decreased percentage of B cells and increased macrophages in chimeric mice lead to enhanced T cell-macrophage interactions after SEB administration and a lethal burst of T cell and macrophage cytokine release. This model will provide insight into cell populations and mechanisms that mediate superantigen-induced toxicity.
Insights
A novel murine chimeric model reveals that staphylococcal enterotoxin B (SEB) toxicity is linked to increased macrophages and decreased B cells. This leads to heightened T cell-macrophage interactions and a lethal cytokine storm, enhancing understanding of superantigen pathogenicity.
Area of Science:
- Immunology
- Microbial Pathogenicity
Background:
- Superantigens like staphylococcal enterotoxin B (SEB) contribute to microbial pathogenicity through poorly understood mechanisms.
- The lack of adequate animal models has hindered research into SEB toxicity and its associated pathogenic processes.
Purpose of the Study:
- To investigate the cytokines and cell populations involved in staphylococcal enterotoxin B (SEB) toxicity using a murine chimeric model.
- To establish a functional animal model for studying superantigen-induced toxicity and immune responses.
Main Methods:
- A murine chimeric model was created using total body irradiation (TBI) and bone marrow transplantation (BMT).
- Chimeric and control mice were challenged with SEB at various time points post-BMT.
- Splenocyte cell populations (CD11b, CD45R, CD4, CD8) and cytokine mRNA expression (IFN-gamma, TNF-alpha, IL-6, IL-1beta, IL-2, IL-10) were analyzed.
- Serum cytokine levels were measured in SEB-challenged mice.
Main Results:
- Chimeric mice exhibited increased CD11b-positive splenocytes (macrophages) and decreased CD45R-positive B cells compared to controls.
- Susceptibility to SEB toxicity was time-dependent, with increased mortality observed 6-8 weeks post-BMT.
- SEB-challenged chimeric mice showed significantly elevated splenocyte mRNA expression and serum levels of key cytokines, including IFN-gamma, IL-6, IL-1beta, and IL-2.
Conclusions:
- The murine chimeric model demonstrates that a decrease in B cells and an increase in macrophages contribute to SEB-induced toxicity.
- Enhanced T cell-macrophage interactions and a subsequent cytokine storm are implicated in SEB pathogenicity.
- This model provides valuable insights into the cellular and molecular mechanisms underlying superantigen-mediated toxicity.