The requirement of glycoprotein C for natural infection and mRNA splicing of UL44 is conserved among the mardiviruses

Xu, Huai

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https://hdl.handle.net/2142/125684 Copy

Description

Title

The requirement of glycoprotein C for natural infection and mRNA splicing of UL44 is conserved among the mardiviruses

Author(s)

Xu, Huai

Issue Date

2024-07-02

Director of Research (if dissertation) or Advisor (if thesis)

Jarosinski, Keith

Doctoral Committee Chair(s)

Jarosinski, Keith

Committee Member(s)

• Rock, Daniel
• Yoo, Dongwan
• Stadtmueller, Beth

Department of Study

Pathobiology

Discipline

VMS - Pathobiology

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• Marek's Disease
• Vaccines
• 301B/1
• HVT
• Horizontal transmission

Abstract

Within the Orthoherpesviridae family, the Alphaherpesvirinae infects many mammals, birds, and other vertebrates, leading to diseases that impact humans and companion and agricultural animals. One notable example is Marek's disease (MD), a lymphoproliferative disease affecting chickens, characterized by high mortality rates, and caused by the Marek's disease herpesvirus (MDV). Infections with virulent strains of MDV result in significant economic losses due to elevated mortality rates, underscoring the importance of prevention and vaccination strategies against MD. MDV primarily targets immune cells, which disseminate the virus to the skin, particularly the feather follicle epithelial (FFE) skin cells. It is within these FFE skin cells that MDV undergoes robust replication, leading to the shedding of the virus from infected chickens into the environment. Subsequently, naïve chickens can contract the virus by inhaling infectious dust and dander. Vaccine strains used against MD include gallid alphaherpesvirus 3 (GaAHV3), a non-oncogenic chicken alphaherpesvirus homologous to MDV, and homologous meleagrid alphaherpesvirus 1 (MeAHV1) or turkey herpesvirus (HVT). Notably, current MD vaccination mitigates clinical symptoms and oncogenesis but does not effectively prevent virus replication, shedding, or the establishment of latency. This poses a significant challenge in disease control, particularly on poultry farms where even vaccinated chickens can perpetuate the shedding of virulent virus. Previous studies in our laboratory have highlighted the crucial role of the alphaherpesviruses conserved glycoprotein C (gC) in facilitating the horizontal transmission of MDV among chickens. Our hypothesis posits that glycoprotein C (gC) represents a promising target for developing recombinant vaccines to provide effective protection against MDV. By targeting gC, we anticipate that such vaccines could offer enhanced efficacy in mitigating clinical symptoms, curtailing viral replication, and impeding virus transmission among chicken populations. The research detailed in this thesis deepens our understanding of the regulation and mechanistic functions of gC proteins in facilitating the horizontal transmission of alphaherpesviruses. First, the requirement of gC for homologous avian herpesviruses during interindividual spread was addressed, showing that gC is also required for an MD vaccine strain 301B/1 that is homologous to MDV. Using classical gene exchange experiments, we confirmed that MDV gC could compensate for 301B/1 gC in horizontal transmission in chickens. Secondly, we confirmed the conserved requirement of HVT gC for horizontal transmission of HVT in turkeys, and MDV gC could also compensate for HVT gC in HVT transmission. Thirdly, we determined that both 301B/1 and HVT produced secreted gC due to mRNA splicing and identified one splicing variant for 301B/1 gC (gC104) and two variants for HVT gC (gC104 and gC145), suggesting that mRNA splicing of avian herpesviruses is highly conserved. Lastly, using the natural virus-host model of Marek’s disease in chickens, we showed dual infection of target cells in chickens with vaccine and virulent virus, allowing recombination or complementation to transpire. These results demonstrate that complementation is a potential mechanism for vaccine-mediated viral evolution, and the potential for complementation should be considered when developing novel vaccines. To summarize, these studies enhance our understanding of herpesvirus pathogenesis, potentially leading to advancements in vaccine development for both human and agricultural diseases.

Graduation Semester

2024-08

Type of Resource

Thesis

Handle URL

https://hdl.handle.net/2142/125684

Copyright and License Information

copyright 2024 Huai Xu

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