| First Author | Tilahun AY | Year | 2011 |
| Journal | PLoS One | Volume | 6 |
| Issue | 2 | Pages | e16764 |
| PubMed ID | 21304813 | Mgi Jnum | J:170914 |
| Mgi Id | MGI:4947890 | Doi | 10.1371/journal.pone.0016764 |
| Citation | Tilahun AY, et al. (2011) Interferon gamma-dependent intestinal pathology contributes to the lethality in bacterial superantigen-induced toxic shock syndrome. PLoS One 6(2):e16764 |
| abstractText | 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-gamma (IFN-gamma), followed by multiple organ dysfunction and often death. As IFN-gamma possesses pro- as well as anti-inflammatory properties, we delineated its role in the pathogenesis of TSS. Antibody-mediated in vivo neutralization of IFN-gamma or targeted disruption of IFN-gamma gene conferred significant protection from lethal TSS in HLA-DR3 transgenic mice. Following systemic high dose SEB challenge, whereas the HLA-DR3.IFN-gamma(+/+) mice became sick and succumbed to TSS, HLA-DR3.IFN-gamma(-/-) mice appeared healthy and were significantly protected from SEB-induced lethality. SEB-induced systemic cytokine storm was significantly blunted in HLA-DR3.IFN-gamma(-/-) 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-gamma(-/-) transgenic mice. However, SEB-induced T cell expansion in the spleens was unaffected and expansion of SEB-reactive TCR Vbeta8(+) CD4(+) and CD8(+) T cells was even more pronounced in HLA-DR3.IFN-gamma(-/-) transgenic mice when compared to HLA-DR3.IFN-gamma(+/+) mice. A systematic histopathological examination of several vital organs revealed that both HLA-DR3.IFN-gamma(+/+) and HLA-DR3.IFN-gamma(-/-) transgenic mice displayed comparable severe inflammatory changes in lungs, and liver during TSS. Remarkably, whereas the small intestines from HLA-DR3.IFN-gamma(+/+) transgenic mice displayed significant pathological changes during TSS, the architecture of small intestines in HLA-DR3.IFN-gamma(-/-) transgenic mice was preserved. In concordance with these histopathological changes, the gut permeability to macromolecules was dramatically increased in HLA-DR3.IFN-gamma(+/+) but not HLA-DR3.IFN-gamma(-/-) mice during TSS. Overall, IFN-gamma 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-gamma in TSS. |
