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Bioinformatics analysis reveals four major hexon variants of human adenovirus type-3 (HAdV-3) as the potential strains for development of vaccine and siRNA-based therapeutics against HAdV-3 respiratory infections.

ABSTRACT: Human adenovirus type 3 (HAdV-3) encompasses 15-87% of all adenoviral respiratory infections. The significant morbidity and mortality, especially among the neonates and immunosuppressed patients, demand the need for a vaccine or a targeted antiviral against this type. However, due to the existence of multiple hexon variants (3Hv-1 to 3Hv-25), the selection of vaccine strains of HAdV-3 is challenging. This study was designed to evaluate HAdV-3 hexon variants for the selection of potential vaccine candidates and the use of hexon gene as a target for designing siRNA that can be used as a therapy. Based on the data of worldwide distribution, duration of circulation, co-circulation and their percentage among all the variants, 3Hv-1 to 3Hv-4 were categorized as the major hexon variants. Phylogenetic analysis and the percentage of homology in the hypervariable regions followed by multi-sequence alignment, zPicture analysis and restriction enzyme analysis were carried out. In the phylogram, the variants were arranged in different clusters. The HVR encoding regions of hexon of 3Hv-1 to 3Hv-4 showed 16 point mutations resulting in 12 amino acids substitutions. The homology in HVRs was 81.81-100%. Therefore, the major hexon variants are substantially different from each other which justifies their inclusion as the potential vaccine candidates. Interestingly, despite the significant differences in the DNA sequence, there were many conserved areas in the HVRs, and we have designed functional siRNAs form those locations. We have also designed immunogenic vaccine peptide epitopes from the hexon protein using bioinformatics prediction tool. We hope that our developed siRNAs and immunogenic vaccine peptide epitopes could be used in the future development of siRNA-based therapy and designing a vaccine against HAdV-3.

SUBMITTER: Panda S

PROVIDER: S-EPMC7308778 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Bioinformatics analysis reveals four major hexon variants of human adenovirus type-3 (HAdV-3) as the potential strains for development of vaccine and siRNA-based therapeutics against HAdV-3 respiratory infections.

Panda Somnath S Banik Urmila U Adhikary Arun K AK

Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases 20200623

Human adenovirus type 3 (HAdV-3) encompasses 15-87% of all adenoviral respiratory infections. The significant morbidity and mortality, especially among the neonates and immunosuppressed patients, demand the need for a vaccine or a targeted antiviral against this type. However, due to the existence of multiple hexon variants (3Hv-1 to 3Hv-25), the selection of vaccine strains of HAdV-3 is challenging. This study was designed to evaluate HAdV-3 hexon variants for the selection of potential vaccine ...[more]

PMID: 32585339

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Project description:Human adenovirus type 3 (HAdV-3) respiratory infections occurs worldwide in both children and adults, leading to severe morbidity and mortality, particularly in the paediatric age group and especially in neonates. During HAdV infection, neutralizing antibodies are formed against the epitopes located in the hyper variable regions (HVRs) of the hexon protein. These neutralizing antibodies provide protection against reinfection by viruses of the same type. Therefore it is reasonable to speculate that variations of HAdV-3 in the HVRs could impair the immunity acquired by previous infection with a different strain with variation in its HVRs. HAdV-3 has recently become the major agent of acute respiratory infection worldwide, being responsible for 15% to 87% of all adenoviral respiratory infections. However, despite the increased prevalence of HAdV-3 as respiratory pathogen, the diversity of hexon proteins in circulating strains remains unexplored. This study was designed to explore the variation in HVRs of hexon among globally distributed strains of HAdV-3 as well as to discover possible relationship among them, thus possibly shedding light on the cause for the increased prevalence of HAdV-3. In this study, for the first time we analysed the hexon proteins of all 248 available strains of HAdV-3 from the NCBI database and compared them with those of the HAdV-3 prototype (GB stain). We found that the HVRs of HAdV-3 strains circulating worldwide were highly heterogeneous and have been mutating continuously since -their original isolation. Based on their immense heterogeneity, the strains can be categorized into 25 hexon variants (3Hv-1 to 3Hv-25), 4 of which (3Hv-1 to 3Hv-4) comprises 80% of the strains. This heterogeneity may explain why HAdV-3 has become the most prevalent HAdVs type worldwide. The heterogeneity of hexon proteins also shows that the development of a vaccine against HAdV-3 might be challenging. The data on hexon variants provided here may be useful for the future epidemiological study of HAdV-3 infection.

Project description:Hepatitis-hydropericardium syndrome (HHS) induced by fowl adenovirus serotype 4 (FAdV-4) has caused huge economic losses to poultry industries. The key genes responsible for different virulence of FAdV-4 strains are not fully elucidated. Previous studies indicated that hexon of pathogenic FAdV-4 has a conserved arginine (R) at position 188, and a conserved isoleucine (I) is present at this position in reported nonpathogenic FAdV-4. Recently, it was reported that R188 of hexon is the determinant site for pathogenicity of the emerging Chinese FAdV-4 strain. However, the role of hexon amino acid 188 (aa188) has not been examined in the nonpathogenic FAdV-4 strain. In this study, three recombinant FAdV-4 viruses, H/H/R188I, O/O/I188R, and H/O/I188R, were constructed by mutating hexon aa188 of FAdV-4 pathogenic strain CH/HNJZ/2015 (H) and nonpathogenic strain ON1 (O), and pathogenicity was assessed in specific-pathogen-free (SPF) chickens. Consistent with previous findings, H/O/I188R exhibited pathogenicity similar to that of CH/HNJZ/2015, yet H/H/R188I induced no mortality. Unexpectedly, all chickens infected with O/O/I188R survived. Postmortem examination of O/O/I188R-infected chickens showed typical lesions of inclusion body hepatitis rather than HHS. Expression of proinflammatory cytokines in CH/HNJZ/2015- and H/O/I188R-infected chickens was significantly higher than that in H/H/R188I-, ON1-, and O/O/I188R-infected chickens. Analysis of predicted hexon protein structures indicated that aa188 mutation leads to conformational changes in the L1 loop of HNJZ-hexon but not in ON1-hexon. In summary, the present study demonstrated that the role of hexon aa188 in the virulence of FAdV-4 varies between different strains. Induction of HHS requires factors aside from hexon aa188 in the emerging Chinese FAdV-4 strain. IMPORTANCE HHS induced by FAdV-4 has caused huge economic losses to the poultry industry. The key determinants for the different virulence of FAdV-4 have not been fully elucidated. Here, we investigated the role of hexon aa188 in FAdV-4 strains with different virulence and showed that the role of hexon aa188 varies in FAdV-4 strains with different genetic contents. The hexon R188 may be the key amino acid for causing inclusion body hepatitis by the pathogenic FAdV-4 strain, and induction of HHS by FAdV-4 may need other viral cofactors. Moreover, the hexon R188I mutation greatly affected the expression of proinflammatory cytokines induced by the pathogenic strain CH/HNJZ/2015, but no significant difference was observed between the nonpathogenic strain ON1 and ON1 with hexon I188R mutation. We found that hexon aa188 mutation induced conformational changes to hexon protein in CH/HNJZ/2015 but not in ON1, which might be the underlying reason for the changing virulence.

Dataset Information

Bioinformatics analysis reveals four major hexon variants of human adenovirus type-3 (HAdV-3) as the potential strains for development of vaccine and siRNA-based therapeutics against HAdV-3 respiratory infections.

Publications

Bioinformatics analysis reveals four major hexon variants of human adenovirus type-3 (HAdV-3) as the potential strains for development of vaccine and siRNA-based therapeutics against HAdV-3 respiratory infections.

Similar Datasets

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