Flaviviruses are a diverse group of emerging arboviruses capable of infecting an extraordinarily broad range of vertebrate and invertebrate hosts. Nearly half of the viruses in this rapidly expanding genus have been reported to be pathogenic for humans, as well as other vertebrates. The spectrum of human disease includes asymptomatic and febrile illnesses, rash, arthralgia, encephalitis and hemorrhagic fever. The recent outbreak of Zika virus (ZIKV) has uncovered pathology in the form of microcephaly and Guillain-Barré syndrome, cementing the importance of flaviviruses as emerging human pathogens. All vector-borne flaviviruses studied thus far have to overcome type I interferon (IFN) antiviral responses in order to replicate and cause disease in vertebrates. The non-structural protein NS5 is a potent and specific antagonist of IFN signaling for human pathogenic flaviviruses such as dengue virus (DENV), yellow fever virus (YFV), West Nile virus (WNV), and tick-borne encephalitis viruses (TBEVs). Intriguingly, each of these viruses exhibits different mechanisms of IFN antagonism, highlighting the complicated evolutionary nature of flaviviruses. This thesis work presents novel insights into the NS5-mediated antagonism of IFN signaling for several underexamined flaviviruses. Notably, all NS5 proteins examined were able to inhibit IFN-induced gene expression in a mammalian system, indicating a functional conservation of IFN antagonism for flavivirus NS5 proteins. However, mechanistically NS5 function was diverse. Of great interest, ZIKV NS5 bound to the human, but not mouse, IFN-regulated transcriptional activator STAT2 and targeted it for proteasomal degradation. This phenomenon may explain the requirement for IFN deficiency in order to observe ZIKV pathogenesis in mice. Furthermore, the mechanism of ZIKV NS5 resembles that of DENV NS5, but not that of its closer relative Spondweni virus (SPOV). However, unlike DENV NS5, ZIKV NS5 did not require the E3 ubiquitin ligase UBR4 to induce STAT2 degradation. Consequently, flavivirus NS5 proteins exhibit a remarkable functional convergence in IFN antagonism, albeit by virus-specific mechanisms. The potent antagonism of human IFN responses by neglected flaviviruses such as SPOV and Usutu virus (USUV), coupled with similar ecologies to that of known human flavivirus pathogens, suggests their potential for broad emergence into the human population.
|Commitee:||Ashour, Joseph, Diamond, Michael S., Lee, Benhur, Lim, Jean, Tortorella, Domenico|
|School:||Icahn School of Medicine at Mount Sinai|
|School Location:||United States -- New York|
|Source:||DAI-B 79/01(E), Dissertation Abstracts International|
|Subjects:||Microbiology, Virology, Immunology|
|Keywords:||Dengue virus, Emerging pathogens, Flavivirus, Interferon, STAT2, Zika virus|
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