Predicting the Next Eye Pathogen: Analysis of a Novel Adenovirus

Robinson, C. M.; Zhou, Xiaohong; Rajaiya, Jaya; Yousuf, Mohammad; Singh, Gurdeep; Deserres, J.; Walsh, Michael P.; Wong, Sallene; Seto, Donald; Dyer, David W.; Chodosh, James; Jones, Mary Smith McCrory

doi:10.1128/mbio.00595-12

Cited by 46 publications

(48 citation statements)

References 47 publications

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“…After primary binding of the fiber knob to its host cell receptor, the RGD motifs on the five-sided penton base capsomer bind to host cellular integrins to mediate endocytosis of the virus (42)(43)(44)(45). We previously showed that the two corresponding hypervariable regions of the penton base open reading frame frequently undergo homologous recombination (14,46), and we have suggested that penton base hypervariable regions may be important to viral pathogenesis (47). Our proteotyping analysis showed that the two hypervariable loops of the penton base protein of the EKC virus HAdV-D56 and the non-EKC virus HAdV-D9 are shared, as was previously shown (10).…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, we tested whether HAdV-D9, with an alanine at fiber knob amino acid 240 similar to the case for EKC viruses, would confer corneal epithelial cell tropism. To perform these studies, we used THE cells, which were previously shown to accurately recapitulate corneal tropism for EKC-associated viruses within HAdV-D (12,37,47). We compared HAdV-D9 entry and early gene expression with those of the EKC viruses HAdV-D37 and -D56.…”

Section: Discussionmentioning

confidence: 99%

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Selection Pressure in the Human Adenovirus Fiber Knob Drives Cell Specificity in Epidemic Keratoconjunctivitis

Ismail

Lee

Dyer

et al. 2016

J Virol

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Human adenoviruses (HAdVs) contain seven species (HAdV-A to -G), each associated with specific disease conditions. Among these, HAdV-D includes those viruses associated with epidemic keratoconjunctivitis (EKC), a severe ocular surface infection. The reasons for corneal tropism for some but not all HAdV-Ds are not known. The fiber protein is a major capsid protein; its C-terminal "knob" mediates binding with host cell receptors to facilitate subsequent viral entry. In a comprehensive phylogenetic analysis of HAdV-D capsid genes, fiber knob gene sequences of HAdV-D types associated with EKC formed a unique clade. By proteotyping analysis, EKC virus-associated fiber knobs were uniquely shared. Comparative structural modeling showed no distinct variations in fiber knobs of EKC types but did show variation among HAdV-Ds in a region overlapping with the known CD46 binding site in HAdV-B. We also found signature amino acid positions that distinguish EKC from non-EKC types, and by in vitro studies we showed that corneal epithelial cell tropism can be predicted by the presence of a lysine or alanine at residue 240. This same amino acid residue in EKC viruses shows evidence for positive selection, suggesting that evolutionary pressure enhances fitness in corneal infection, and may be a molecular determinant in EKC pathogenesis. IMPORTANCEViruses adapt various survival strategies to gain entry into target host cells. Human adenovirus (HAdV) types are associated with distinct disease conditions, yet evidence for connections between genotype and cellular tropism is generally lacking. Here, we provide a structural and evolutionary basis for the association between specific genotypes within HAdV species D and epidemic keratoconjunctivitis, a severe ocular surface infection. We find that HAdV-D fiber genes of major EKC pathogens, specifically the fiber knob gene region, share a distinct phylogenetic clade. Deeper analysis of the fiber gene revealed that evolutionary pressure at crucial amino acid sites has a significant impact on its structural conformation, which is likely important in host cell binding and entry. Specific amino acids in hot spot residues provide a link to ocular cell tropism and possibly to corneal pathogenesis. Human adenoviruses (HAdVs) are major causes of respiratory disease, gastroenteritis, and keratoconjunctivitis (1-4). HAdV infections are also a major concern in immunocompromised hosts, with fatality rates as high as 55% (5). There are 72 HAdVs currently genotyped in GenBank, which are classified into seven species (HAdV-A to -G) as determined by whole-genome analysis. The majority (n ϭ 47) belong to HAdV-D, including types 8, 37, 53, 54, 56, and 64 (6-12). Each of these has been associated with epidemic keratoconjunctivitis (EKC), a highly contagious ocular surface infection (13). HAdV-D evolves by homologous recombination within genes encoding the major HAdV capsid proteins (14). For example, type 64 (previously typed as 19a) is a recombinant with types 19, 22, and 37 in the hexon, penton ba...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Selection Pressure in the Human Adenovirus Fiber Knob Drives Cell Specificity in Epidemic Keratoconjunctivitis

Ismail

Lee

Dyer

et al. 2016

J Virol

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“…Switching of the hexon variable regions to a low seroprevalence epitope of HAdV-48 (37) and producing the novel combination of the epitope-containing capsid proteins, represented as P65H48F60, may have increased the success rate of host infection by HAdV_Chiba_E086/2012 since the low seroprevalence indicates that only a small number of hosts have experienced HAdV-48-like viruses. The change to the HAdV-GT60-like fiber may have altered the tropism of this virus from bronchoalveolar (as in HAdV-GT59) (6) to ocular (34). If this virus is an adaptive form, it would have the potential to cause epidemic ocular infections.…”

Section: Discussionmentioning

confidence: 99%

“…Although originally isolated from a respiratory infection, an experimental study has suggested that HAdV-GT60 may have a potential corneal tropism (34). In addition, the fiber knob has been reported to mediate the attachment of the virus to the receptor on the host cell (35,36), thus implying that the fiber is a determinant of tissue tropism of the virus.…”

Section: Discussionmentioning

confidence: 99%

A Novel Complex Recombinant Form of Type 48-Related Human Adenovirus Species D Isolated in Japan

et al. 2014

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SUMMARY:Recently, new genotypes of human adenoviruses (HAdVs) have been reported and many of them have been found to be recombinant forms of different known types of HAdV species D (HAdV-D). The objective of this study was to document the evolutionary features of a novel isolate (HAdV_ Chiba_E086/2012) obtained from the eye swab of a patient with conjunctivitis in Japan. Viral DNA was extracted from the isolate to sequence the whole genome by the Sanger method and aligned with available genome sequences of HAdV-Ds. The phylogenetic trees of the nucleotide sequences of the penton base, hexon, and fiber genes and the E3 region showed that HAdV_Chiba_E086/2012 is closest to HAdV genotype 65 (HAdV-GT65), HAdV-48, HAdV-GT60 and HAdV-22 at 98z, 99z, 95z and 98z identity, respectively, suggesting that this isolate is a novel recombinant form to be designated as P65H48F60. Further phylogenetic and recombination analyses of the genome alignment of the new isolate implied that nested recombination events involving HAdV-GT59, GT65, 48, GT60, 22, and some ancestral lineages or their close relatives have shaped its genome. These results showed that HAdV_ Chiba_E086/2012 is the first HAdV-48-related HAdV found in Japan, which has the most complicated evolutionary history among the known HAdVs so far.

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“…Además, pueden comprometer los sistemas gastrointestinal, ocular, renal, entre otros, (3) con billones de personas infectadas a nivel mundial . (4,5) Comprenden 65 genotipos (HAdV-1 a HAdV-65) , de los cuales los primeros 51 tipos fueron caracterizados en base al tipo específico de (6,7) neutralización mediada por antisuero y los demás fueron designados por análisis bioinformático de (4) secuencias . Los genotipos se agrupan en siete (8) especies, denominadas HAdV-A a HAdV-G .…”

Section: Introductionunclassified

Diversity of adenoviruses detected in children less than 5 years of age hospitalized with lower acute respiratory infection in Paraguay, 2010-2013

Barrios

Russomando

Espínola

2016

Pediatr. (Asunción)

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Diversidad de adenovirus detectados en niños menores de 5 años hospitalizados por infección respiratoria aguda baja en Paraguay, 2010Paraguay, -2013 Diversity of adenoviruses detected in children less than 5 years of age hospitalized with lower acute respiratory infection in Paraguay, 2010Paraguay, -2013 (1)Julio C. Barrios , Graciela Russomando , Emilio E. Espínola RESUMEN Palabras clave:Los adenovirus humanos (HAdV) causan una diversidad de patologías que pueden ser leves o incluso mortales en pacientes vulnerables. Su evolución ocurre conforme actúa una presión de selección; por ejemplo, la recombinación genética genera cepas híbridas que pueden ser más infectivas o más patogénicas que las parentales. Este estudio buscó determinar la diversidad de HAdV circulantes en niños paraguayos menores de 5 años hospitalizados por infección respiratoria aguda baja, mediante el uso de herramientas de biología molecular y bioinformática, para lo cual fueron amplificados los genes hexon, penton y fibra en 26 muestras de aspirados nasofaríngeos. Se demostró la circulación de tres especies: B (4/26), C (21/26), y D (1/26), así como también eventos de recombinación en el aislado correspondiente a HAdV-D, al menos con tres genotipos distintos (D49, D9 y D15). Los HAdV-D están asociados a enfermedades gastrointestinales, oculares y, menos comúnmente a infecciones respiratorias. Sin embargo, recientemente se han reportado cambios en el comportamiento de estos virus debido a recombinación, lo que les permite expandir su repertorio de células huésped. Estos datos amplían los conocimientos acerca de la diversidad genética de HAdV en el Paraguay y apoyan fuertemente la importancia de los análisis genómicos mediante herramientas bioinformáticas en la vigilancia epidemiológica de las cepas recombinantes emergentes de HAdV.Infección respiratoria aguda baja, adenovirus, secuenciación ADN, análisis bioinformático, recombinación. ABSTRACT Keywords:Adenoviruses cause a variety of diseases that range from mild to fatal in vulnerable patients. Its evolution occurs as a process of selection pressure; for example, genetic recombination generates intermediate strains that can be more infectious or pathogenic than parental strains. This study sought to determine the diversity of circulating adenoviruses in Paraguayan children less than 5 years of age hospitalized with acute lower respiratory infection, by using molecular biology and bioinformatics tools, though amplification of penton, hexon and fiber genes in 26 samples of nasopharyngeal aspirates. It was demonstrated the circulation of three species: B (4/26), C (21/26), and D (1/26), as well as recombination events corresponding to the HAdV-D isolate, with at least three different genotypes (D49, D9 y D15). The HAdV-D are associated with gastrointestinal or ocular diseases, and less commonly with respiratory infections. Recently, however, it has been reported changes in behavior of these viruses due to recombination, allowing them to expand their host cell repertoire. These data extend the ...

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Predicting the Next Eye Pathogen: Analysis of a Novel Adenovirus

Cited by 46 publications

References 47 publications

Selection Pressure in the Human Adenovirus Fiber Knob Drives Cell Specificity in Epidemic Keratoconjunctivitis

Selection Pressure in the Human Adenovirus Fiber Knob Drives Cell Specificity in Epidemic Keratoconjunctivitis

A Novel Complex Recombinant Form of Type 48-Related Human Adenovirus Species D Isolated in Japan

Diversity of adenoviruses detected in children less than 5 years of age hospitalized with lower acute respiratory infection in Paraguay, 2010-2013

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