Antagonism of Host Interferon Response by Emerging Positive-Strand RNA Viruses

• Author / Creator

  Ishida, Ray

• Positive strand RNA ((+)ssRNA) viruses are some of the most important pathogens that impact the public health, economy, and quality of life. The interferon (IFN) response plays a critical role in innate immune response targeting (+)ssRNA viruses, which in turn have evolved various strategies to circumvent this response in order to establish infection. In this thesis, I investigated how two emerging (+)ssRNA viruses, Mayaro virus (MAYV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), affect the host IFN response and determined the mechanisms by which specific viral proteins antagonize this pathway.
  MAYV infection was found to significantly impair the induction phase of the IFN response and mapping studies revealed that non-structural protein 2 (NSP2) was responsible for this effect. Expression of MAYV NSP2 depleted DNA-directed RNA polymerase II subunit A (Rpb1) and transcription initiation factor II E subunit 2 (TFIIE2) which are indispensable for host mRNA synthesis. This indicated that NSP2-mediated transcriptional shutoff was the primary mechanism by which MAYV blocks IFN induction.
  Induction of IFNs and IFN-stimulated genes (ISGs) were also blocked during SARS-CoV- 2 infection. The viral proteins NSP1 and nucleocapsid (N) both blocked the IFN response indicating that SARS-CoV-2 employs multiple mechanisms to subvert the host antiviral defenses. Translational shutoff by NSP1 resulted in depletion of key IFN signaling proteins, such as tyrosine kinase 2 (Tyk2) and signal transducer and activator of transcription 2 (STAT2).
  Together, this research provides new insights into the mechanisms by which two recently emerged (+)ssRNA viruses antagonize the host IFN response. Current findings should be taken into account when developing and administering antiviral therapeutics.

• Subjects / Keywords

  • interferon
  • alphavirus
  • coronavirus
  • Mayaro virus
  • SARS-CoV-2

• Graduation date

  Spring 2022

• Type of Item

  Thesis

• Degree

  Master of Science

• DOI

  https://doi.org/10.7939/r3-vv4p-y627

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.