عنوان :
انتشارات :
ProQuest Dissertations and Theses
سال :2015
زبان :
English
شماره سند :
9781339262918
موضوع : Microbiology , Virology , Immunology
نویسندگان :
Speer, Scott David
S.
D.
Scott
David
Speer
Speer, Scott David
سایر :
Copyright ProQuest Dissertations Publishing 2015
چکیده :
ISG15 is an interferon (IFN)-?/?-inducible protein that exists as a free molecule and conjugated to target proteins (ISGylation). In vivo studies in mice have demonstrated a critical role for ISG15 in antiviral immunity. By contrast, in humans, ISG15 has been shown to have critical functions, but not in antiviral immunity. Free extracellular ISG15 is essential in IFN-γ-dependent anti-mycobacterial immunity, and free intracellular ISG15 is essential for the USP18-mediated downregulation of type-I IFN signaling. We describe USP18 deficient humans, who like mice, cannot control IFN-α/β signaling and show hyperISGylation profile molecularly (the second function of USP18 is to remove ISG15 from ISGylated proteins). These phenotypes are completely rescued with complementation with WT USP18 allele. We also describe ISG15 -deficient patients, who unlike Isg15 -deficient mice, display no enhanced susceptibility to viruses in vivo. On the contrary, ISG15 -deficient fibroblasts displayed enhanced antiviral protection. The complementation with WT ISG15 restored viral replication to WT control levels. Species divergence in antiviral immunity when comparing ISG15 deficient humans to Isg15 deficient mice, is explained by ISG15 stabilization of USP18 in humans, but not in mice. In summary, while USP18 function appears to be conserved cross species, this is not the case for ISG15. Unlike mice, ISG15-deficient individuals present with gain-of-function in antiviral immunity at the expense of increased susceptibility to mycobacteria and auto-immunity.
فهرست :
پایان نامه پروکوئست 2015
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