scholarly journals Predicting the Next Eye Pathogen: Analysis of a Novel Adenovirus

mBio ◽  
2013 ◽  
Vol 4 (2) ◽  
Author(s):  
Christopher M. Robinson ◽  
Xiaohong Zhou ◽  
Jaya Rajaiya ◽  
Mohammad A. Yousuf ◽  
Gurdeep Singh ◽  
...  
Keyword(s):  
Systems Biology ◽  
Genetic Recombination ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Genetic Alterations ◽  
Laboratory Simulation ◽  
Penton Base ◽  
Emerging Viruses ◽  
Evolutionary Mechanisms

ABSTRACTFor DNA viruses, genetic recombination, addition, and deletion represent important evolutionary mechanisms. Since these genetic alterations can lead to new, possibly severe pathogens, we applied a systems biology approach to study the pathogenicity of a novel human adenovirus with a naturally occurring deletion of the canonical penton base Arg-Gly-Asp (RGD) loop, thought to be critical to cellular entry by adenoviruses. Bioinformatic analysis revealed a new highly recombinant species D human adenovirus (HAdV-D60). A synthesis ofin silicoand laboratory approaches revealed a potential ocular tropism for the new virus.In vivo, inflammation induced by the virus was dramatically greater than that by adenovirus type 37, a major eye pathogen, possibly due to a novel alternate ligand, Tyr-Gly-Asp (YGD), on the penton base protein. The combination of bioinformatics and laboratory simulation may have important applications in the prediction of tissue tropism for newly discovered and emerging viruses.IMPORTANCEThe ongoing dance between a virus and its host distinctly shapes how the virus evolves. While human adenoviruses typically cause mild infections, recent reports have described newly characterized adenoviruses that cause severe, sometimes fatal human infections. Here, we report a systems biology approach to show how evolution has affected the disease potential of a recently identified novel human adenovirus. A comprehensive understanding of viral evolution and pathogenicity is essential to our capacity to foretell the potential impact on human disease for new and emerging viruses.

scholarly journals Genomic characterization of a novel human adenovirus type 31 recombinant in the hexon gene

2011 ◽  
Vol 92 (12) ◽  
pp. 2770-2775 ◽  
Author(s):  
Yuki Matsushima ◽  
Hideaki Shimizu ◽  
Tung Gia Phan ◽  
Hiroshi Ushijima
Keyword(s):  
Acute Gastroenteritis ◽  
Recombinant Adenovirus ◽  
Genetic Recombination ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Close Relative ◽  
Hexon Gene ◽  
Penton Base ◽  
Genomic Characterization

A novel human recombinant adenovirus of species A (HAdV-A31 MZ) was isolated from a patient with acute gastroenteritis in Japan. The complete genome of HAdV-A31 strain MZ contains 33 776 bp. Analysis of the hexon gene of HAdV-A31 MZ indicated that its hexon sequence is the result of a genetic recombination between those of HAdV-A31 and a close relative to HAdV-A12. The recombination sites were found around the border of hypervariable loops 1 and 2 in the hexon gene, which are the most important determinants for virus neutralization. Loops 1 and 2 of this virus were genetically related to HAdV-A12, whereas all other parts of the genome were highly similar to HAdV-A31. In order to understand the evolution of adenoviruses correctly and to avoid misidentification of HAdV types, we recommend characterizing not only the hexon gene, but also the penton base and fiber genes.

The penton base of human adenovirus type 3 has the RGD motif

Gene ◽  
1994 ◽  
Vol 146 (2) ◽  
pp. 257-259 ◽  
Author(s):  
Alain Cuzange ◽  
Jadwiga Chroboczek ◽  
Bernard Jacrot
Keyword(s):  
Human Adenovirus ◽  
Adenovirus Type ◽  
Penton Base ◽  
Rgd Motif ◽  
Type 3

scholarly journals In Vitro and In Vivo Evaluation of Human Adenovirus Type 49 as a Vector for Therapeutic Applications

Viruses ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1483
Author(s):  
Emily A. Bates ◽  
John R. Counsell ◽  
Sophie Alizert ◽  
Alexander T. Baker ◽  
Natalie Suff ◽  
...  
Keyword(s):  
Viral Vector ◽  
Ex Vivo ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Cell Types ◽  
In Vivo Evaluation ◽  
In Vivo Biodistribution ◽  
Adenovirus Type 5

The human adenovirus phylogenetic tree is split across seven species (A–G). Species D adenoviruses offer potential advantages for gene therapy applications, with low rates of pre-existing immunity detected across screened populations. However, many aspects of the basic virology of species D—such as their cellular tropism, receptor usage, and in vivo biodistribution profile—remain unknown. Here, we have characterized human adenovirus type 49 (HAdV-D49)—a relatively understudied species D member. We report that HAdV-D49 does not appear to use a single pathway to gain cell entry, but appears able to interact with various surface molecules for entry. As such, HAdV-D49 can transduce a broad range of cell types in vitro, with variable engagement of blood coagulation FX. Interestingly, when comparing in vivo biodistribution to adenovirus type 5, HAdV-D49 vectors show reduced liver targeting, whilst maintaining transduction of lung and spleen. Overall, this presents HAdV-D49 as a robust viral vector platform for ex vivo manipulation of human cells, and for in vivo applications where the therapeutic goal is to target the lung or gain access to immune cells in the spleen, whilst avoiding liver interactions, such as intravascular vaccine applications.

Determination of the nucleotide sequence for the penton-base gene of human adenovirus type 5

Gene ◽  
1988 ◽  
Vol 69 (1) ◽  
pp. 153-157 ◽  
Author(s):  
Rita Neumann ◽  
Jadwiga Chroboczek ◽  
Bernard Jacrot
Keyword(s):  
Nucleotide Sequence ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Penton Base ◽  
Adenovirus Type 5

scholarly journals Replication Properties of Human Adenovirus In Vivo and in Cultures of Primary Cells from Different Animal Species

2006 ◽  
Vol 80 (7) ◽  
pp. 3549-3558 ◽  
Author(s):  
Christian Jogler ◽  
Dennis Hoffmann ◽  
Dirk Theegarten ◽  
Thomas Grunwald ◽  
Klaus Überla ◽  
...  
Keyword(s):  
Viral Load ◽  
Animal Species ◽  
A549 Cells ◽  
Human Adenovirus ◽  
Fold Increase ◽  
Adenovirus Type ◽  
Adenoviral Vectors ◽  
Treatment Modalities ◽  
Late Gene Expression

ABSTRACT Oncolytic adenoviruses have emerged as a promising approach for the treatment of tumors resistant to other treatment modalities. However, preclinical safety studies are hampered by the lack of a permissive nonhuman host. Screening of a panel of primary cell cultures from seven different animal species revealed that porcine cells support productive replication of human adenovirus type 5 (Ad5) nearly as efficiently as human A549 cells, while release of infectious virus by cells from other animal species tested was diminished by several orders of magnitude. Restriction of productive Ad5 replication in rodent and rabbit cells seems to act primarily at a postentry step. Replication efficiency of adenoviral vectors harboring different E1 deletions or mutations in porcine cells was similar to that in A549 cells. Side-by-side comparison of the viral load kinetics in blood of swine and mice injected with Ad5 or a replication-deficient adenoviral vector failed to provide clear evidence for virus replication in mice. In contrast, evidence suggests that adenovirus replication occurs in swine, since adenoviral late gene expression produced a 13.5-fold increase in viral load in an individual swine from day 3 to day 7 and 100-fold increase in viral DNA levels in the Ad5-infected swine compared to the animal receiving a replication-deficient adenovirus. Lung histology of Ad5-infected swine revealed a severe interstitial pneumonia. Although the results in swine are based on a small number of animals and need to be confirmed, our data strongly suggest that infection of swine with human adenovirus or oncolytic adenoviral vectors is a more appropriate animal model to study adenoviral pathogenicity or pharmacodynamic and toxicity profiles of adenoviral vectors than infection of mice.

scholarly journals In Vitro and In Vivo Evaluation of Human Adenovirus Type 49 as a Vector for Therapeutic Applications

2021 ◽  
Author(s):  
Emily A. Bates ◽  
John R. Counsell ◽  
Sophie Alizert ◽  
Alexander T. Baker ◽  
Natalie Suff ◽  
...  
Keyword(s):  
Viral Vector ◽  
Ex Vivo ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Cell Types ◽  
In Vivo Evaluation ◽  
In Vivo Biodistribution ◽  
Adenovirus Type 5

The human adenovirus phylogenetic tree is split across seven species (A-G). Species D adenoviruses offer potential advantages for gene therapy applications, with low rates of preexisting immunity detected across screened populations. However, many aspects of the basic virology of species D, such as their cellular tropism, receptor usage and in vivo biodistribution profile, remain unknown. Here, we have characterized human adenovirus type 49 (HAdV-D49), a relatively understudied species D member. We report that HAdV-D49 does not appear to use a single pathway to gain cell entry but appears able to interact with various surface molecules for entry. As such, HAdV-D49 can transduce a broad range of cell types in vitro, with variable engagement of blood coagulation FX. Interestingly, when comparing in vivo biodistribution to adenovirus type 5, HAdV-D49 vectors show reduced liver targeting whilst maintaining transduction of lung and spleen. Overall, this presents HAdV-D49 as a robust viral vector platform for ex vivo manipulation of human cells and for in vivo applications where the therapeutic goal is to target the lung or gain access to immune cells in the spleen whilst avoiding liver interactions, such as intravascular vaccine applications.

scholarly journals Integrin alpha v beta 5 selectively promotes adenovirus mediated cell membrane permeabilization.

1994 ◽  
Vol 127 (1) ◽  
pp. 257-264 ◽  
Author(s):  
T J Wickham ◽  
E J Filardo ◽  
D A Cheresh ◽  
G R Nemerow
Keyword(s):  
Human Adenovirus ◽  
Adenovirus Type ◽  
Membrane Permeabilization ◽  
Host Cells ◽  
Penton Base ◽  
Subsequent Step ◽  
Cell Membrane Permeabilization ◽  
Subsequent Event ◽  
Alpha V Beta 3

Human adenovirus type 2 (Ad2) enters host cells by receptor-mediated endocytosis, an event mediated by the virus penton base binding to cell surface integrins alpha v beta 3 and alpha v beta 5. While both alpha v integrins promote virus internalization, alpha v beta 5 is involved in the subsequent event of membrane permeabilization. Cells transfected with the beta 5 or beta 3 subunit, expressing either alpha v beta 5 and alpha v beta 3, respectively, were capable of supporting Ad2 infection to varying degrees. In this case, cells expressing alpha v beta 5 were significantly more susceptible to Ad2-induced membrane permeabilization, as well as to Ad2 infection, than cells expressing alpha v beta 3. Adenovirus-mediated gene delivery was also more efficient in cells expressing alpha v beta 5. These results suggest that the interaction of alpha v beta 5 with Ad2 penton base facilitates the subsequent step of virus penetration into the cell. These studies provide evidence for the involvement of a cellular receptor in virus-mediated membrane permeabilization and suggest a novel biological role for integrin alpha v beta 5 in the infectious pathway of a human adenovirus.

scholarly journals Bacterial RecA Protein Promotes Adenoviral Recombination duringIn VitroInfection

mSphere ◽  
2018 ◽  
Vol 3 (3) ◽  
Author(s):  
Jeong Yoon Lee ◽  
Ji Sun Lee ◽  
Emma C. Materne ◽  
Rahul Rajala ◽  
Ashrafali M. Ismail ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Hot Spots ◽  
Genetic Recombination ◽  
Reca Protein ◽  
Human Adenovirus ◽  
Penton Base ◽  
Content Type ◽  
E Coli ◽  
Recombination Hot Spots ◽  
Loop 2

ABSTRACTAdenovirus infections in humans are common and sometimes lethal. Adenovirus-derived vectors are also commonly chosen for gene therapy in human clinical trials. We have shown in previous work that homologous recombination between adenoviral genomes of human adenovirus species D (HAdV-D), the largest and fastest growing HAdV species, is responsible for the rapid evolution of this species. Because adenovirus infection initiates in mucosal epithelia, particularly at the gastrointestinal, respiratory, genitourinary, and ocular surfaces, we sought to determine a possible role for mucosal microbiota in adenovirus genome diversity. By analysis of known recombination hot spots across 38 human adenovirus genomes in species D (HAdV-D), we identified nucleotide sequence motifs similar to bacterial Chi sequences, which facilitate homologous recombination in the presence of bacterial Rec enzymes. These motifs, referred to here as ChiAD, were identified immediately 5′ to the sequence encoding penton base hypervariable loop 2, which expresses the arginine-glycine-aspartate moiety critical to adenoviral cellular entry. Coinfection with two HAdV-Ds in the presence of anEscherichia colilysate increased recombination; this was blocked in a RecA mutant strain,E. coliDH5α, or upon RecA depletion. Recombination increased in the presence ofE. colilysate despite a general reduction in viral replication. RecA colocalized with viral DNA in HAdV-D-infected cell nuclei and was shown to bind specifically to ChiADsequences. These results indicate that adenoviruses may repurpose bacterial recombination machinery, a sharing of evolutionary mechanisms across a diverse microbiota, and unique example of viral commensalism.IMPORTANCEAdenoviruses are common human mucosal pathogens of the gastrointestinal, respiratory, and genitourinary tracts and ocular surface. Here, we report finding Chi-like sequences in adenovirus recombination hot spots. Adenovirus coinfection in the presence of bacterial RecA protein facilitated homologous recombination between viruses. Genetic recombination led to evolution of an important external feature on the adenoviral capsid, namely, the penton base protein hypervariable loop 2, which contains the arginine-glycine-aspartic acid motif critical to viral internalization. We speculate that free Rec proteins present in gastrointestinal secretions upon bacterial cell death facilitate the evolution of human adenoviruses through homologous recombination, an example of viral commensalism and the complexity of virus-host interactions, including regional microbiota.

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