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Bioinformatic and Functional Analysis of Fowl Adenovirus Genomic Sequences

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Title: Bioinformatic and Functional Analysis of Fowl Adenovirus Genomic Sequences
Author: Griffin, Bryan
Department: Department of Pathobiology
Program: Pathobiology
Advisor: Nagy, Éva
Abstract: Fowl adenoviruses (FAdVs) are the aetoiologic agents of inclusion body hepatitis (IBH), and certain isolates of species Fowl aviadenovirus C are the aetiologic agent of inclusion body hepatitis/hydropericardium syndrome (IBH/HPS). Recombinant fowl adenoviruses have been successfully developed as veterinary vaccine vectors. However, insufficient definitions of the protein-coding and noncoding regions and an incomplete understanding of virus-host interactions limits the progress of next-generation vectors. This work describes the first complete genome sequence of FAdV-4 of species Fowl aviadenovirus C. The protein-coding potential of FAdV-4 was characterized using the Bio-Dictionary-based Gene Finder (BDGF) together with an evaluation of sequence conservation among other FAdV species. Employing these criteria, 46 potential protein-coding ORFs were identified. Of these, 33 and 13 ORFs were assigned high and low protein-coding potential, respectively. Notable putative genes with high protein-coding capacity included the previously unreported fiber 1, hypothetical 10.3K, and hypothetical 10.5K genes. Several of the small ORFs less than 300 nt in length that were assigned low coding potential contributed to upstream ORFs (uORFs) in important mRNAs. Additional work describes the downregulation of surface and total MHC-I (BF2) in FAdV-infected cells. Representative isolates from species Fowl aviadenovirus C, D, and E downregulated cell-surface expression of MHC-I in chicken hepatoma cells at 12 hours post-infection, resulting in approximately 71%, 14%, and 11% of the level of MHC-I on the surface of mock-infected cells, respectively. Further, this work reports that FAdV-9 downregulated surface MHC-I by a mechanism dependent on early transcription unit 1 (FE1) within the left-end terminal genomic region and a lysosomal-dependent mechanism that is encoded outside of FE1 and lead to a reduction of total MHC-I levels. Subsequently, it was determined via mutagenesis of the FAdV-9 molecular clone that the genomic region within FE1 predicted to encode ORF1C contributed to the downregulation of cell surface MHC-I in vitro. Further, it was demonstrated that chickens infected with mutant virus lacking ORF1C shed significantly less virus than chickens infected with wild type FAdV-9. These studies provide important new information about immune evasion of FAdVs and will enhance our understanding of IBH and allow the progress of nextgeneration FAdV-based vector systems.
Date: 2016-01
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