Bhalla, Nishank
(2016)
Evasion and Resistance of Host Antiviral Defense pathways by Alphaviruses.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
The Alphavirus genus consists of positive-sense single stranded RNA viruses which cause millions of annual infections, and are classified as arthritogenic (Sindbis (SINV) and Chikungunya virus (CHIKV)) or encephalitic (Venezuelan (VEEV) and eastern equine encephalitis viruses (EEEV)) based on disease phenotype. The nature, severity and outcome of disease following infection by a particular alphavirus are primarily dependent on evasion of or resistance to the Interferon-α/β (IFN-α/β) upregulated antiviral state. In mice, induced serum IFN-α/β levels are highest following VEEV infection, lower following SINV infection, and negligible after EEEV or CHIKV infection. SINV or CHIKV cause a self-limiting, non-fatal infection in mice with functional IFN α/β responses, suggesting limited antagonism of the IFN-α/β response, while infection with EEEV or VEEV is lethal. Whereas EEEV avoids both IFN-α/β and antiviral state induction via suppression of myeloid cell replication and lymphoid tissue dissemination, VEEV infection is associated with extensive systemic replication that occurs despite rapid induction of serum IFN-α/β, suggesting successful replication despite upregulation of antiviral effectors. However, viral determinants of this differential sensitivity of various alphaviruses to IFN-α/β are unknown.
In this study I have investigated the relative sensitivity of SINV, CHIKV, EEEV and VEEV to the IFN-α/β induced antiviral state, and found that VEEV is most resistant to the activities of antiviral effectors expressed either collectively or individually. I mapped this activity to the nonstructural protein-expressing region of the genome, and determined that VEEV nonstructural protein 2 (nsP2) induced translation shutoff is critical for the antiviral state resistance of VEEV. I definitively separated virus induced transcription and translation shutoff as independent activities, and identified the viral proteins mediating these activities for multiple alphaviruses. Furthermore, I demonstrated that expression of nsP2 alone is sufficient to block Signal Transducer and Activator of Transcription 1 (STAT1) phosphorylation, and that viral infection induces proteasome-mediated degradation of Janus Kinase 1 (JAK1). Additionally, I demonstrate the role of IRF7 in host antiviral response induction following alphavirus infection. Overall, I have delineated the interactions of multiple alphaviruses with host antiviral mechanisms, and illustrated the different strategies that closely related alphaviruses can use to successfully overcome the IFN-α/β response.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| Date: |
6 December 2016 |
| Date Type: |
Publication |
| Defense Date: |
30 August 2016 |
| Approval Date: |
6 December 2016 |
| Submission Date: |
28 September 2016 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
170 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Molecular Virology and Microbiology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Alphaviruses, Interferon, Translation shutoff, Transcription shutoff, Nonstructural protein 2 |
| Date Deposited: |
06 Dec 2016 20:54 |
| Last Modified: |
07 Dec 2016 06:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/29757 |
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