Interferon gamma-dependent intestinal pathology contributes to the lethality in bacterial superantigen- induced Toxic shock syndrome

Ashenafi Y. Tilahun, Marah Holz, Tsung Teh Wu, Chella S. David, Govindarajan Rajagopalan

Research output: Contribution to journalArticle

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Abstract

Toxic shock syndrome (TSS) caused by the superantigen exotoxins of Staphylococcus aureus and Streptococcus pyogenes is characterized by robust T cell activation, profound elevation in systemic levels of multiple cytokines, including interferon-γ (IFN-γ), followed by multiple organ dysfunction and often death. As IFN-γ possesses pro- as well as anti-inflammatory properties, we delineated its role in the pathogenesis of TSS. Antibody-mediated in vivo neutralization of IFN-γ or targeted disruption of IFN-γ gene conferred significant protection from lethal TSS in HLA-DR3 transgenic mice. Following systemic high dose SEB challenge, whereas the HLA-DR3.IFN-γ+/+ mice became sick and succumbed to TSS, HLA-DR3.IFN- γ-/- mice appeared healthy and were significantly protected from SEB-induced lethality. SEB-induced systemic cytokine storm was significantly blunted in HLA-DR3.IFN-γ-/- transgenic mice. Serum concentrations of several cytokines (IL-4, IL-10, IL-12p40 and IL-17) and chemokines (KC, rantes, eotaxin and MCP-1) were significantly lower in HLA-DR3.IFN-γ-/- transgenic mice. However, SEB-induced T cell expansion in the spleens was unaffected and expansion of SEB-reactive TCR Vb8+ CD4+ and CD8+ T cells was even more pronounced in HLA-DR3.IFN-γ-/- transgenic mice when compared to HLA-DR3.IFN-γ+/+ mice. A systematic histopathological examination of several vital organs revealed that both HLA-DR3.IFN-γ+/+ and HLA-DR3.IFN-γ-/- transgenic mice displayed comparable severe inflammatory changes in lungs, and liver during TSS. Remarkably, whereas the small intestines fromHLA-DR3.IFN-γ+/+ transgenic mice displayed significant pathological changes during TSS, the architecture of small intestines in HLA-DR3.IFN-γ-/- transgenic mice was preserved. In concordance with these histopathological changes, the gut permeability to macromolecules was dramatically increased in HLA-DR3.IFN-γ+/+ but not HLA-DR3.IFN-γ-/- mice during TSS. Overall, IFN-γ seemed to play a lethal role in the immunopathogenesis of TSS by inflicting fatal small bowel pathology. Our study thus identifies the important role for IFN-γ in TSS.

Original languageEnglish (US)
Article numbere16764
JournalPLoS One
Volume6
Issue number2
DOIs
StatePublished - 2011

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superantigens
septic shock
Superantigens
Poisons
Pathology
interferons
Septic Shock
interferon-gamma
HLA-DR3 Antigen
Interferons
Interferon-gamma
Transgenic Mice
mice
genetically modified organisms
T-cells
cytokines
T-lymphocytes
Cytokines
T-Lymphocytes
lethal genes

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Interferon gamma-dependent intestinal pathology contributes to the lethality in bacterial superantigen- induced Toxic shock syndrome. / Tilahun, Ashenafi Y.; Holz, Marah; Wu, Tsung Teh; David, Chella S.; Rajagopalan, Govindarajan.

In: PLoS One, Vol. 6, No. 2, e16764, 2011.

Research output: Contribution to journalArticle

Tilahun, Ashenafi Y. ; Holz, Marah ; Wu, Tsung Teh ; David, Chella S. ; Rajagopalan, Govindarajan. / Interferon gamma-dependent intestinal pathology contributes to the lethality in bacterial superantigen- induced Toxic shock syndrome. In: PLoS One. 2011 ; Vol. 6, No. 2.
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