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 Vβ8+ 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 from HLA-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.
Highlights
Toxic shock syndrome (TSS) is a serious systemic illness caused by the Gram-positive cocci, Staphylococcus aureus or Streptococcus pyogenes [1,2]
HLA-DR3 transgenic mice challenged with staphylococcal enterotoxin B (SEB) and treated with rat IgG isotype control antibodies succumbed to TSS
Only one out of six HLA-DR3 transgenic mice challenged with SEB and treated with anti-IFN-c (400 mg/mouse) succumbed to TSS
Summary
Toxic shock syndrome (TSS) is a serious systemic illness caused by the Gram-positive cocci, Staphylococcus aureus or Streptococcus pyogenes [1,2]. Toxic shock syndrome caused by S. aureus and S. pyogenes could be either menstrual or non-menstrual, has a rapid onset and can result in mortality, if not treated promptly [4,5,6]. The T cells activated by SAg rapidly produce large amounts of cytokines and chemokines resulting in a sudden surge in the systemic levels of these biological mediators. This process, called systemic inflammatory response syndrome (SIRS), may lead to multiple organ dysfunction syndrome or MODS, wherein several vital organs within the body fail to perform their physiological functions. Exposure to weaponized SEB can causes a syndrome identical to TSS and can cause mortality
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