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Gamma-Interferon Attenuates Yellow Fever Virus Vaccine Strain 17D

Lam, Long Kwan Metthew (2018) Gamma-Interferon Attenuates Yellow Fever Virus Vaccine Strain 17D. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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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
CreatorsEmailPitt UsernameORCID
Lam, Long Kwan Metthewmetthew.lam@gmail.comlol150000-0001-9700-4988
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairKlimstra, William
Committee MemberAmbrose,
Committee MemberBarratt-Boyes,
Committee MemberMorel, Penelope
Committee MemberShlomchik, Mark
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


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