title: Evidence of molecular evolution driven by recombination events influencing tropism in a novel human adenovirus that causes epidemic keratoconjunctivitis.
abstract: In 2005, a human adenovirus strain (formerly known as HAdV-D22/H8 but renamed here HAdV-D53) was isolated from an outbreak of epidemic keratoconjunctititis (EKC), a disease that is usually caused by HAdV-D8, -D19, or -D37, not HAdV-D22. To date, a complete change of tropism compared to the prototype has never been observed, although apparent recombinant strains of other viruses from species Human adenovirus D (HAdV-D) have been described. The complete genome of HAdV-D53 was sequenced to elucidate recombination events that lead to the emergence of a viable and highly virulent virus with a modified tropism. Bioinformatic and phylogenetic analyses of this genome demonstrate that this adenovirus is a recombinant of HAdV-D8 (including the fiber gene encoding the primary cellular receptor binding site), HAdV-D22, (the epsilon determinant of the hexon gene), HAdV-D37 (including the penton base gene encoding the secondary cellular receptor binding site), and at least one unknown or unsequenced HAdV-D strain. Bootscanning analysis of the complete genomic sequence of this novel adenovirus, which we have re-named HAdV-D53, indicated at least five recombination events between the aforementioned adenoviruses. Intrahexon recombination sites perfectly framed the epsilon neutralization determinant that was almost identical to the HAdV-D22 prototype. Additional bootscan analysis of all HAdV-D hexon genes revealed recombinations in identical locations in several other adenoviruses. In addition, HAdV-D53 but not HAdV-D22 induced corneal inflammation in a mouse model. Serological analysis confirmed previous results and demonstrated that HAdV-D53 has a neutralization profile representative of the epsilon determinant of its hexon (HAdV-D22) and the fiber (HAdV-D8) proteins. Our recombinant hexon sequence is almost identical to the hexon sequences of the HAdV-D strain causing EKC outbreaks in Japan, suggesting that HAdV-D53 is pandemic as an emerging EKC agent. This documents the first genomic, bioinformatic, and biological descriptions of the molecular evolution events engendering an emerging pathogenic adenovirus.
authors.affiliation: Department of Bioinformatics and Computational Biology, George Mason University, Manassas, VA, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Walsh
authors.forename: Ashish
authors.initials: A
authors.lastname: Chintakuntlawar
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Robinson
authors.forename: Ijad
authors.initials: I
authors.lastname: Madisch
authors.forename: Balázs
authors.initials: B
authors.lastname: Harrach
authors.forename: Nolan R
authors.initials: NR
authors.lastname: Hudson
authors.forename: David
authors.initials: D
authors.lastname: Schnurr
authors.forename: Albert
authors.initials: A
authors.lastname: Heim
authors.forename: James
authors.initials: J
authors.lastname: Chodosh
authors.forename: Donald
authors.initials: D
authors.lastname: Seto
authors.forename: Morris S
authors.initials: MS
authors.lastname: Jones
mesh_terms: D000260:Adenoviruses, Human / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D019295:Computational Biology / Q000379:methods; D019143:Evolution, Molecular; D016679:Genome, Viral; D006801:Humans; D007637:Keratoconjunctivitis / Q000209:etiology* / Q000821:virology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008957:Models, Genetic; D008969:Molecular Sequence Data; D010802:Phylogeny; D011995:Recombination, Genetic; D012689:Sequence Homology, Nucleic Acid