Browsing by Subject "Interferon-gamma"
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Item Neutrophil-Derived IFN-γ in Toxoplasma gondii Infection and Innate Immunity(2014-11-19) Sturge, Carolyn Rowena; van Oers, Nicolai S. C.; Yuan, Dorothy; Zhang, Chengcheng "Alec"; Koh, Andrew Y.; Yarovinsky, FelixInterferon-gamma (IFN-γ) is a major cytokine that is critical for host resistance to a broad range of intracellular pathogens. Production of IFN-γ by Natural Killer (NK) and T cells is initiated by the recognition of pathogens through Toll-like receptors (TLRs). In an experimental model of toxoplasmosis we have identified the presence of a non-lymphoid source of IFN-γ that was particularly evident in the absence of TLR-mediated recognition of Toxoplasma gondii. Flow-cytometry and morphological examinations of non-NK/non-T IFN-γ-positive cells identified neutrophils as the cell type capable of producing IFN-γ. Selective elimination of neutrophils in TLR11-/- mice infected with the parasite resulted in acute susceptibility similar to that observed in IFN-γ-deficient mice. These data show that neutrophils are a biologically significant source of IFN-γ during T. gondii infection. Additionally, we investigated the role of neutrophil IFN-γ in another intracellular infection, Salmonella typhimurium, and found that neutrophils were also IFN-γ-positive. Examination of neutrophils in different locations in a mouse model revealed that they all expressed low amounts of IFN-γ regardless of infection status. In particular, the bone marrow niche contained an IFN-γ+ population that was negative for the Ly-6G marker characteristic of mature neutrophils in peripheral tissues. Recent work defining neutrophil developmental stages by flow-cytometry allowed us to discern that precursor neutrophils at the promyelocyte stage (Ly-6G negative) were positive for IFN-γ. Furthermore, neutrophil-derived IFN-γ was prestored in granules during neutrophil lineage development although the mechanisms behind this phenomena are not yet understood. This work, combined with the recent work of other laboratories, suggests that neutrophils can have defined phenotypes and cytokine production similar to that of T cells or Innate Lymphoid cells (ILCs). These findings have broad implications for all disease states where neutrophils are the first responders to infections.Item Paneth Cell-Dependent Intestinal Homeostasis During T. Gondii Infection(2017-04-14) Burger, Elise Sylvie; Hooper, Lora V.; Yarovinsky, Felix; van Oers, Nicolai S. C.; Burstein, Ezra; Brown, Michael S.; Amatruda, James F.The intestinal epithelial barrier faces the arduous task of constantly monitoring and controlling the diverse bacteria which colonize the gut. Key for this balance are the Paneth cells, highly specialized secretory epithelial cells in the intestinal crypts which secrete anti-microbial peptides to regulate the microbiota. Breakdown of the symbiotic host-microbe relationship, possibly due to Paneth cell dysfunction, leads to intestinal pathologies such as inflammatory bowel disease (IBD) and infection. The protozoan parasite Toxoplasma gondii triggers severe small intestinal immunopathology that recapitulates many characteristics of IBD such as elevated IFN-g and microbiota-mediated inflammation, along with disappearance of Paneth cells. However, little is known about what happens to these Paneth cells and if their loss exacerbates inflammation. In this study, we have generated a number of fluorescent Paneth cell-specific reporter mice to demonstrate that acute T. gondii infection leads to Paneth cell death by an IFN-g-dependent pathway. Our results also revealed that constitutive elimination of Paneth cells does not enhance susceptibility to T. gondii infection, enhance inflammation, or increase damage to the intestinal epithelium, suggesting that Paneth cell retention at the peak of inflammation may be detrimental and these cells may be targeted for controlled elimination early during T. gondii infection. We also demonstrate that the microbiota triggers basal Paneth cell-specific autophagy via induction of IFN-g. Deletion of Atg5 in Paneth cells resulted in exaggerated intestinal inflammation characterized by the complete destruction of the intestinal crypts seen in pan-epithelial Atg5 deficient mice. An evaluation of Atg5 in intestinal organoids and in T. gondii-infected mice revealed that lack of functional autophagy in Paneth cells resulted in increased sensitivity to TNF, leading to exaggerated microbiota and IFN-g-dependent intestinal immunopathology. Our results reveal that Paneth cell expression of Atg5 is essential for tissue protection against cytokine-mediated immunopathology during acute gastrointestinal infection. Together, these findings have broad implications for the role of Paneth cells during both acute infection and chronic intestinal inflammation.Item [UT Southwestern Medical Center News](2013-07-10) Wormser, Deborah