Genomic analysis of a large set of currently—and historically—important human adenovirus pathogens

Abstract

Human adenoviruses (HAdVs) are uniquely important “model organisms” as they have been used to elucidate fundamental biological processes, are recognized as complex pathogens, and are used as remedies for human health. As pathogens, HAdVs may effect asymptomatic or mild and severe symptomatic disease upon their infection of respiratory, ocular, gastrointestinal, and genitourinary systems. High-resolution genomic data have enhanced the understanding of HAdV epidemiology, with recombination recognized as an important and major pathway in the molecular evolution and genesis of emergent HAdV pathogens. To support this view and to actualize an algorithm for identifying, characterizing, and typing novel HAdVs, we determined the DNA sequence of 95 isolates from archives containing historically important pathogens and collections housing currently circulating strains to be sequenced. Of the 85 samples that were completely sequenced, 18 novel recombinants within species HAdV-B and D were identified. Two HAdV-D genomes were found to contain novel penton base and fiber genes with significant divergence from known molecular types. In this data set, we found additional isolates of HAdV-D53 and HAdV-D58, two novel genotypes recognized recently using genomics. This supports the thesis that novel HAdV genotypes are not limited to “one-time” appearances of the prototype but are of importance in HAdV epidemiology. These data underscore the significance of lateral genomic transfer in HAdV evolution and reinforce the potential public health impact of novel genotypes of HAdVs emerging in the population.

A Zoonotic Adenoviral Human Pathogen Emerged through Genomic Recombination among Human and Nonhuman Simian Hosts

“…This virus was among a collection of HAdVs gifted to A. Heim (Institut für Virologie, Medizinische Hochschule, Hannover, Germany) by T. Adrian and R. Wigand (Institut for Medizinische Mikrobiologie und Hygiene, Abteilung for Virologie, Universitätskliniken, Homburg, Germany) upon their retirement. Genomic DNA was prepared as described earlier (65), with the virus recovered from a freezer stock and propagated on A549 cells, and DNA was isolated and shipped to the J. Craig Venter Institute (JCVI) Genomics Sequencing Center for Infectious Diseases (Rockville, MD) and sequenced using Illumina HiSeq and Roche 454 GS-FLX platforms as described previously (12).…”

“…Genomes used for these analyses are archived in GenBank: HAdV-A12 (AC_000005), HAdV-B7 (AY594255), HAdV-B14 (AY803294), HAdV-B16 (AY601636), HAdV-B21 (AY601633), HAdV-C5 (AC_000008), HAdV-D9 (AJ854486), HAdV-E4 prototype (AY594253), HAdV-E4FS1 (also known as NHRC 42606; AY599835), HAdV-F40 (NC_001454), HAdV-G52 (DQ923122), SAdV-B21 (AC_000010), SAdV-E22 (AY530876), SAdV-E25 (AC_000011), SAdV-B27.1 (FJ025909), SAdV-B35.1 (FJ025912.1), and SAdV-B35.2 (FJ025910.1). HAdV-B76 was assigned GenBank accession number KF633445 (12).…”

“…1953 (8,9). There are currently 90 accepted genotypes characterized by whole-genome analysis (http:// hadvwg.gmu.edu/) (10)(11)(12); these are parsed into seven species (A to G) based on biological, clinical, and genomic attributes (13). Ironically, they are used as gene and epitope delivery vectors as well as oncolytic agents (14), despite their roles as human pathogens.…”

“…Applying whole-genome analysis has demonstrated recombination as another important molecular evolution mechanism by which novel HAdV pathogens arise, e.g., genotypes 53 and 64, recombinants that present epitopes of nonpathogens but are pathogens (44,45), and genotype 55, a recombinant that presents the epitope of a kidney pathogen but is a respiratory pathogen (46). Taking advantage of a collaborative project between our Adenovirus Genome Sequencing Consortium and the J. Craig Venter Institute (JCVI) Genomic Sequencing Center for Infectious Diseases, historically intriguing HAdV pathogens were selected from three archives to ascertain additional recombinant pathogens that may have been misidentified with serological methods (12). One virus, originally named "Ad 21 ϩ 16H16," was an emergent pathogen that caused pneumonia and rapid progression to death in a 6-year-old boy (27).…”

Virus–Host Coevolution with a Focus on Animal and Human DNA Viruses

“…Exactly in HAdV-D strains it is often observed that homologous recombination has a driving force in adenovirus evolution (Crawford-Miksza and Schnurr 1996;Gonzalez et al 2015;Ismail et al 2018a;Kaján et al 2017;Robinson et al 2013;Walsh et al 2009). Predominantly, intraspecies recombination events are common, but intergenus recombinants have also been reported already: the head domain of the porcine adenovirus 5 (genus Mastadenovirus) fibre seems to be of atadenoviral origin (Nagy et al 2002), though a porcine atadenovirus has not been discovered yet.…”