Lam, Long Kwan Metthew
(2018)
Gamma-Interferon Attenuates Yellow Fever Virus Vaccine Strain 17D.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
The genus Flavivirus in the family Flaviviridae consists of many medically important vector- borne viruses, including West Nile, yellow fever (YFV), dengue, and Zika viruses. In the recent decade, these viruses have emerged beyond their historical geographical boundaries, causing outbreaks and posing a threat to public health systems. Despite their medical importance, licensed, effective drugs and/or vaccines against these viruses are lacking, with the exception of the YFV. The live attenuated vaccine for YFV, strain 17D, is among the most effective viral vaccines ever developed. While this vaccine is relatively avirulent and highly immunogenic, its attenuated phenotype was derived by blind passage of a virulent strain, leaving the mechanisms of attenuation unknown. Moreover, 17D has been engineered as a delivery vector for heterologous antigens. Importantly, the successful and safe use of 17D as a vaccine vector and the development of live attenuated vaccines (LAVs) to related flaviviruses requires an understanding of the molecular mechanisms leading to 17D attenuation.
Using subcutaneous infection of interferon signaling-deficient mouse models of wild type yellow fever virus (WT YFV) pathogenesis and 17D-mediated immunity, we have investigate the role of type II interferon (IFN-g) in attenuation of 17D in vivo. We found that in the absence of type I IFN (IFN-a/b), IFN-g restricted replication of 17D but not WT YFV by 2 days post- infection. In this context, IFN-g responses protected 17D-infected animals from mortality, largely restricted the virus to lymphoid organs, and eliminated viscerotropic disease signs such as
steatosis in the liver and inflammatory cell infiltration into the spleen. In contrast, WT YFV caused a disseminated infection, gross liver pathology, and rapid death of the animals. We also uncovered a mechanism by which IFN-g can restrict 17D in human vacinees. IFN-g treatment of myeloid cells suppressed the replication of 17D significantly more than that of WT YFV in vitro, suggesting a direct differential effect on 17D virus replication. Overall, our results indicate that an important mechanism of 17D attenuation in vivo is enhanced sensitivity to IFN-g-stimulated responses elicited early after infection.
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| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
30 January 2018 |
| Date Type: |
Publication |
| Defense Date: |
22 January 2018 |
| Approval Date: |
30 January 2018 |
| Submission Date: |
30 January 2018 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
144 |
| 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: |
Yellow fever virus
17D
live attenuated vaccines
interferon |
| Date Deposited: |
30 Jan 2018 18:49 |
| Last Modified: |
30 Jan 2018 18:49 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/33750 |
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