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Xiaohong Zhou, Christopher M. Robinson, Jaya Rajaiya, Donald Seto, Morris S. Jones, David W. Dyer, James Chodosh; Mistyping of Human Adenovirus Type 19 Associated with Epidemic Keratoconjunctivitis. Invest. Ophthalmol. Vis. Sci. 2012;53(14):6157.
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© ARVO (1962-2015); The Authors (2016-present)
Human adenovirus species D type 19 (HAdV-D19) is associated with epidemic keratoconjunctivitis (EKC), an acute and highly inflammatory infection of the cornea and conjunctiva with considerable morbidity. However, confusion exists regarding the origins and corneal tropism of HAdV-D19. The prototype virus (HAdV-D19p) has not been isolated from patients with EKC, while a virus identified later with the identical serologic determinant is a significant EKC pathogen.
High throughput sequencing, global pairwise genome alignment, and bioinformatics analysis was performed on HAdV-D19p and three strains of HAdV-D19 isolated directly from patients with EKC, and compared to a previously characterized clinical isolate (HAdV-D19 (C)) and the closely related HAdV-D37. Corneas of C57BL/6J mice were injected intrastromally with HAdV-D19p, HAdV-D19 (C), or virus-free dialysis buffer, and assessed by clinical examination, flow cytometry, and ELISA. Confocal microscopy and real-time PCR of infected corneal cell cultures were used to assess viral entry and DNA replication, respectively.
Whole genome-wide comparisons revealed near 100% sequence identity between HAdV-D19 (C) and the three EKC clinical isolates newly sequenced. In contrast, HAdV-D19p nucleotide sequence diverged from clinical EKC isolates in the penton base, E3, and fiber protein coding regions. Simplot analysis showed that EKC-associated HAdV-D19 is actually a naturally occurring recombinant of HAdV-D37, HAdV-D22, and HAdV-D19p, the latter contributing only the hexon gene, which contains the serotype determinant. Surprisingly, HAdV-D19p induced significant inflammation in the C57BL/6J mouse adenovirus stromal keratitis model, but infection of corneal cell lines showed that HAdV-D19p does not infect human corneal epithelial cells.
HAdV-D19 strains associated with EKC originated from a recombination between HAdV-D19p, HAdV-D37, and HAdV-D22. Although highly inflammatory in the corneal stroma, HAdV-D19p is not infectious for corneal epithelial cells, thus explaining its lack of an association with keratitis. Based on recently revised GenBank criteria, EKC-associated HAdV-D19 should be retyped.
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