The impact of tacrolimus on the immunopathogenesis of staphylococcal enterotoxin-induced systemic inflammatory response syndrome and pneumonia

• Published in: Microbes and infection 2012-06, Vol.14 (6), p.528-536
• Main Authors: Tilahun, Ashenafi Y., Karau, Melissa J., Clark, Chad R., Patel, Robin, Rajagopalan, Govindarajan
• Format: Article
• Language: English
• Subjects: Animals; Bacteriology; Biological and medical sciences; Cell activation; Cell proliferation; Chemokines; Cytokines; Cytokines - biosynthesis; Cytokines - immunology; Digestive tract; Enterotoxins - immunology; Exotoxins; Fundamental and applied biological sciences. Psychology; Histocompatibility antigen HLA; HLA class II transgenic mice; HLA-DR3 Antigen - genetics; Humans; Immune system; Immunopathogenesis; Immunosuppressive agents; Immunosuppressive Agents - pharmacology; Immunosuppressive Agents - therapeutic use; Lymphocyte Activation - drug effects; Lymphocytes T; Mice; Mice, Transgenic; Microbiology; Miscellaneous; Pneumonia; Pneumonia, Staphylococcal - drug therapy; Pneumonia, Staphylococcal - immunology; Pneumonia, Staphylococcal - physiopathology; Prophylaxis; Rodents; Sepsis; Shock; Staphylococcus aureus; Staphylococcus aureus - drug effects; Staphylococcus aureus - pathogenicity; Superantigens; Superantigens - immunology; Systemic Inflammatory Response Syndrome - drug therapy; Systemic Inflammatory Response Syndrome - immunology; Systemic Inflammatory Response Syndrome - physiopathology; T lymphocytes; T-Lymphocytes - immunology; Tacrolimus; Tacrolimus - pharmacology; Tacrolimus - therapeutic use; Transgenic mice; Treatment Outcome
• ISSN: 1286-4579; 1769-714X
• DOI: 10.1016/j.micinf.2012.01.001

Staphylococcal superantigens (SAg) are a family of potent exotoxins produced by Staphylococcus aureus. They play an important role in the pathogenesis of staphylococcal shock and pneumonia by causing a robust activation of the immune system and eliciting a strong surge in systemic cytokine and chemokine levels. Given the biological functions of SAg, we evaluated the efficacy of tacrolimus, a potent immunosuppressive agent, in the prophylaxis and therapy of staphylococcal TSS and pneumonia using human leukocyte antigen (HLA)-DR3 transgenic mice. Tacrolimus significantly inhibited staphylococcal SAg induced T cell activation in vitro. In vivo, tacrolimus significantly suppressed the SAg-induced elevation in serum cytokine and chemokine levels when given prophylactically, when administered immediately or even 2 h following systemic SAg challenge. Paradoxically, neither the prophylactic nor post-exposure treatment with tacrolimus protected mice from lethal SAg-induced TSS. A closer examination revealed that tacrolimus failed to suppress SAg-induced T cell proliferation and systemic pathology, including gut dysfunction. Tacrolimus also failed to protect from lethal pneumonia induced by a SAg-producing S. aureus strain. Thus, our study showed that even though T cell activation by SAg plays a major role in the immunopathogenesis of TSS and pneumonia, tacrolimus alone has no beneficial effect.