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 ε 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 ε 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 ε 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.
Highlights
Epidemic keratoconjunctivitis (EKC), characterized by inflammation of the conjunctiva and cornea, produces a sudden onset of acute follicular conjunctivitis and stromal keratitis and is a worldwide problem causing significant and sometime lasting morbidity [1]
D22/H8) demonstrated that portions of the penton and fiber genes were similar to Human adenoviruses (HAdVs)-D37 and HAdV-D8, respectively [19]; suggesting that this disease causing virus was the result of recombination
The initial report of HAdV-D53 described that this novel, possibly emergent disease-causing, strain comprised a HAdV-D22 strain that had recombined with HAdV-D8 and HAdV-D37 [19]
Summary
Epidemic keratoconjunctivitis (EKC), characterized by inflammation of the conjunctiva and cornea, produces a sudden onset of acute follicular conjunctivitis and stromal keratitis and is a worldwide problem causing significant and sometime lasting morbidity [1]. 52 human adenovirus (HAdV) genotypes have been characterized and classified according to their immunochemical properties, nucleic acid similarities, hexon and fiber protein characteristics, biological properties, and phylogenetic analysis, and placed in the genus Mastadenovirus [6,7] These 52 adenovirus genotypes that infect humans are classified into seven species (Human adenovirus A to G) [6,8] and are known to cause a range of diseases specific to the tropisms of the viruses: keratoconjunctivitis (HAdV-D8, HAdV-D19, and HAdV-D37) [9,10], gastroenteritis (HAdVA31, HAdV-F40, HAdV-F41, and HAdV-G52) [6], acute respiratory disease (HAdV-B3, HAdV-E4, HAdV-B7, HAdVB14, and HAdV-B21) [5], and perhaps obesity (HAdV-D36) [11]
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