Biomedical Sciences ETDs

Publication Date

Summer 7-10-2019

Abstract

Human adenovirus type 4 (HAdV-E4) is a causative agent of acute respiratory disease and conjunctivitis worldwide. Two major lineages of HAdV-E4 genomic variants have been identified by their distinct BamHI restriction profiles: prototype-like (p-like) strains and the a-like genomic variants. Recent molecular epidemiology studies have shown a predominance of a-like genomic variants detected in association with disease which suggests a-like strains have a fitness advantage or they may be more pathogenic. The impact of HAdV-E4 intratypic genetic variability on in vitro and in vivo phenotypes relevant to pathogenesis is a major gap in knowledge. I hypothesize that HAdV-E4 comprises two distinct evolutionary lineages that differ in their in vitro growth and in vivo pathogenetic phenotypes. Whole genome sequences (WGS) from 45 HAdV-E4 strains isolated between 1953 and 2015 clustered into two phylogroups: phylogroup I (PG I) includes the p-like strains and phylogroup II (PG II) comprises the a-like variants. Bioinformatics analysis of WGS identified divergence at multiple genomic loci that may contribute to differences in in vitro and in vivo pathogenic phenotypes. In cell culture, PG I strains formed larger plaques, exhibited an enhanced cell killing phenotype, and replicated faster compared to PG II strains. Interestingly, infection with a PG II strain resulted in more severe pulmonary pathology in a cotton rat model of HAdV respiratory infection. The results of this study set the foundation for future efforts to elucidate the molecular basis of HAdV-E4 pathogenesis by comparing these in vitro and in vivo phenotypes using isogenic mutant viruses.

Keywords

Adenovirus type 4, genetic diversity, phylogroup, pathogenesis

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Committee Member (Chair)

Bryce Chackerian

Second Committee Member

Adriana Kajon

Third Committee Member

Michelle Ozbun

Fourth Committee Member

Diane Lidke

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