Intratypic Genetic Variability of Human Adenovirus Type 4: Implication for Viral Pathogenesis
Year: 2019
Type: article
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.
Author: Camden R. Bair
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2995922183