Human Adenovirus Type Research Articles

Comparative analysis of the impact of 40 adenovirus types on dendritic cell activation and CD8+ T cell proliferation capacity for the identification of favorable immunization vector candidates.

For the development of new adenovirus (AdV)-based vectors, it is important to understand differences in immunogenicity. In a side-by-side in vitro analysis, we evaluated the effect of 40 AdV types covering human AdV (HAdV) species A through G on the expression of 11 activation markers and the secretion of 12 cytokines by AdV-transduced dendritic cells, and the effect on CD8+ T cell proliferation capacity. We found that the expression of activation markers and cytokines differed widely between the different HAdV types, and many types were able to significantly impair the proliferation capacity of CD8+ T cells. Univariate and multivariate regression analyses suggested an important role of type I interferons in mediating this suppression of CD8+ T cells, which we confirmed experimentally in a proliferation assay using a type I interferon receptor blocking antibody. Using Bayesian statistics, we calculated a prediction model that suggests HAdV types HAdV-C1, -D8, -B7, -F41, -D33, -C2, -A31, -B3 and -D65 as the most favorable candidates for vaccine vector development.

Selenadiazole Inhibited Adenovirus-Induced Apoptosis through the Oxidative-Damage-Mediated Bcl-2/Stat 3/NF-κB Signaling Pathway.

Human adenovirus type 7 (HAdV7) infection causes severe pneumonia, yet there are still no breakthroughs in treatment options for adenovirus, and the road to antiviral drug development faces major challenges. We attempted to find new drugs and we stumbled upon one: selenadiazole. Selenadiazole has been shown to have significant anti-tumor effects due to its unique chemical structure and drug activity. However, its effectiveness against viruses has not been evaluated yet. In our study, selenadiazole also showed superior antiviral activity. In vitro experiments, selenadiazole was able to inhibit adenovirus-mediated mitochondrial-oxidative-damage-related apoptosis, and in in vivo experiments, selenadiazole was able to inhibit apoptosis by modulating the apoptotic signaling pathway Bcl-2/Stat3/NF-κB, etc., and was able to largely attenuate adenovirus-infection-induced pneumonia and lung injury in mice. This study aims to describe a new antiviral treatment option from the perspective of anti-adenovirus-mediated oxidative stress and its associated apoptosis and to provide theoretical guidance for the treatment of clinical adenovirus infection to a certain extent.

The Virucidal Effect of the Chlorination of Water at the Initial Phase of Disinfection May Be Underestimated If Contact Time Calculations Are Used.

For the microbiological safety of drinking water, disinfection methods are used to remove or inactivate microorganisms. Chlorine and chlorine dioxide are often used as disinfectants in drinking water treatment plants (DWTPs). We investigated the effectiveness of these chemicals in inactivate echovirus 30 (E30), simian 11 rotavirus (RV SA11), and human adenovirus type 2 (HAdV2) in purified water from a DWTP. Within two minutes of contact, chlorine dioxide inactivated E30 by 4-log10, RV SA11 by 3-log10, and HAdV2 could not be detected, while chlorine reduced E30 by 3-log10, RV SA11 by 2-3log10, and HAdV2 by 3-4log10. However, viral genomes could be detected for up to 2 h using qPCR. The CT method, based on a combination of disinfectant concentration and contact time, during such a short initial phase, is problematic. The high concentrations of disinfectant needed to neutralize organic matter may have a strong immediate effect on virus viability. This may lead to the underestimation of disinfection and overdosing of disinfectants in water with organic contamination. These results are useful for the selection of disinfection systems for reuse of treated wastewater and in the risk assessment of water treatment processes using chlorine and chlorine dioxide.

An easy pill to swallow: oral recombinant vaccines for the 21st century.

Oral vaccines have a distinctive advantage of stimulating immune responses in the mucosa, where numerous pathogens gain entry and cause disease. Although various efforts have been attempted to create recombinant mucosal vaccines that provoke strong immunogenicity, the outcomes in clinical trials have been weak or inconsistent. Therefore, next-generation mucosal vaccines are needed that are more immunogenic. Here, we discuss oral vaccines with an emphasis on a next-generation mucosal vaccine that utilizes a nonreplicating human recombinant adenovirus type-5 (rAd5) vector. Numerous positive clinical results investigating oral rAd5 vaccines are reviewed, with a summary of the immunogenicity and efficacy results for specific vaccine indications of influenza, norovirus, and SARS-CoV-2. The determination of correlates of protection for oral vaccination and the potential impact this novel vaccine formulation may have on disease transmission are also discussed. In summary, successful oral vaccination can be accomplished and would have major public health benefits if approved.

1014TiP Efficacy and safety of recombinant human adenovirus type 5 injection combined with transhepatic arterial embolization sequential thermal ablation for medium-and high-risk recurrent liver cancer: a prospective, open-label, randomized controlled study

1014TiP Efficacy and safety of recombinant human adenovirus type 5 injection combined with transhepatic arterial embolization sequential thermal ablation for medium-and high-risk recurrent liver cancer: a prospective, open-label, randomized controlled study

757P The efficacy and safety of recombinant human adenovirus type 5 (H101) intra-tumor therapy in patients with recurrent or metastatic cervical cancer: A prospective, open-label, single-arm study

757P The efficacy and safety of recombinant human adenovirus type 5 (H101) intra-tumor therapy in patients with recurrent or metastatic cervical cancer: A prospective, open-label, single-arm study

Alterations in Lung Carcinoma Cells and Cell-Derived Extracellular Vesicles after Human Adenovirus Type 5 Administration

Human adenoviruses (HAdVs) affect the respiratory system of healthy individuals and people with pre-existing health conditions. These highly infectious viruses can alter a myriad of cellular and pathophysiological processes. HAdVs can modulate their infection ability and pathogenicity by regulating extracellular vesicles (EVs) formation and function. EVs are nanovesicles that facilitate intracellular communication, cell signaling/trafficking, and immune regulation. We propose that HAdVs can exploit EV formation, secretion, and release various pathways to promote infection and transmission between neighboring cells. In the present study, we explored the impact of HAdV serotype 5 (HAdV-5) on the A549-epithelial carcinoma cells and EVs derived from A549 cells. A549 cells were cultured in an exosome-depleted medium and administered different concentrations of HAdV-5 at varying time points. The effect of HAdV-5 infection on A549 cells and A549-derived EVs was determined by 4’,6-diamidino2-phenylindole (DAPI) stain, 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay, electron microscopy, particle size, zeta potential analysis, immunosorbent analysis, total RNA levels, and total protein content. Our findings illustrated that HAdV-5 reduces A549-cell viability and promotes variations within the protein content of A549 cells. Our data explicitly demonstrated that HAdV-5 significantly altered EV numbers, biogenesis, and composition. These findings suggest that HAdV-5 modulates EVs’ biological properties and physiological functions in human lung carcinoma cells.

Molecular Prevalence and Genotype Distribution of Human Adenovirus in Iranian Children with Gastroenteritis

Objective We determined the molecular prevalence and genotype distribution of human adenovirus (HAdV) among children under five years of age with gastroenteritis in Iran. Methods One hundred stool samples from children hospitalized were tested by PCR for adenovirus, and some of the positive samples were sequenced to determine the specific genotype. Results HAdV DNA was found in 15 samples (15%). The highest and the lowest prevalence of HAdV was observed in the age groups 24–60 months (n = 6; 40%) and 7–12 months (n = 2; 13.3%), respectively (p = 0.01). Nine HAdV-positive samples were sequenced, of which four isolates were HAdV type 2 and five isolates were HAdV type 41. Conclusion HAdV was most common in the 24–60-month-old children. Of the samples sequenced, we found only types 2 and 41. Our results show that in addition to HAdV types 40 and 41, HAdV type 2 may also play a role in causing gastroenteritis in children.

VISN: virus instance segmentation network for TEM images using deep attention transformer.

The identification of viruses from negative staining transmission electron microscopy (TEM) images has mainly depended on experienced experts. Recent advances in artificial intelligence have enabled virus recognition using deep learning techniques. However, most of the existing methods only perform virus classification or semantic segmentation, and few studies have addressed the challenge of virus instance segmentation in TEM images. In this paper, we focus on the instance segmentation of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) and other respiratory viruses and provide experts with more effective information about viruses. We propose an effective virus instance segmentation network based on the You Only Look At CoefficienTs backbone, which integrates the Swin Transformer, dense connections and the coordinate-spatial attention mechanism, to identify SARS-CoV-2, H1N1 influenza virus, respiratory syncytial virus, Herpes simplex virus-1, Human adenovirus type 5 and Vaccinia virus. We also provide a public TEM virus dataset and conduct extensive comparative experiments. Our method achieves a mean average precision score of 83.8 and F1 score of 0.920, outperforming other state-of-the-art instance segmentation algorithms. The proposed automated method provides virologists with an effective approach for recognizing and identifying SARS-CoV-2 and assisting in the diagnosis of viruses. Our dataset and code are accessible at https://github.com/xiaochiHNU/Virus-Instance-Segmentation-Transformer-Network.

Adenovirus-Associated Urethritis, a Not So Uncommon Entity. A Review of 91 Cases.

Human adenovirus (HAdV) is likely an underdiagnosed cause of urethritis, although it was already associated with urethritis in descriptions published more than 40 years ago. Differential clinical features of this entity, such as meatitis, conjunctivitis, and a predominance of mononuclear white blood cells in first-void urine and/or urethral smear, can be useful to increase diagnostic suspicion. We retrospectively studied 91 episodes of HAdV-associated urethritis diagnosed for 9 years and 6 months after optimizing efforts to detect the pathogen mainly in patients with features suggestive of this condition. Dysuria was the main symptom (84%), whereas meatitis was observed in 34% of cases. Furthermore, 40% of patients had conjunctivitis. Human adenovirus type D was the most prevalent HAdV (56%), although HAdV-C6, a type not previously associated with urethritis, was observed in 12 patients (13%). Urethritis due to HAdV is not uncommon, and it is important to screen for it to avoid unnecessary treatments, contact tracing studies, and checkups. The use of multiplex polymerase chain reaction assays that include HAdV, for the diagnosis of urethritis, would raise awareness of its role in this entity.

Intranasal inoculation of female BALB/c mice with replication-deficient human adenovirus type 5 expressing SARS-CoV‐2 nucleocapsid protein aggravates lung pathology upon re-encountering the antigen

Preclinical studies indicate that SARS-CoV-2 nucleocapsid (N)-based vaccines, along with other viral protein(s), confer protection in various animal models against infection by SARS-CoV-2 ancestral virus and variants of concern. However, the optimal vaccination procedure and the role of N-specific host adaptive immune responses remain elusive. Here, we report that intranasal inoculation with replication-deficient human adenovirus type 5 expressing SARS-CoV‐2 N protein (Ad5-N) conferred no protection in the lung of female BALB/c mice upon re-encountering the antigen, either by 10-fold Ad5-N re-exposure or sublethal infection of mouse-adapted SARS-CoV-2. By contrast, this procedure led to aggravated lung pathology with more necroptotic CD3+ T cells and Ly6G+ granulocytes, which was associated with the accumulation of IFN‐γ‐expressing antigen-experienced CD4+ and CD8+ T cells. These findings pre-caution the clinical application of this vaccination procedure. Furthermore, our data suggest that excessive host adaptive immune responses against N protein contributes to COVID-19 pathogenesis.

Etiological Study of Acute Conjunctivitis Caused by Human Adenovirus in Shanxi Province, China, between 2016 and 2019.

Human adenovirus (HAdV) is the primary cause of acute conjunctivitis. To improve our understanding of the etiology of adenoviral conjunctivitis, ocular samples were collected from 160 conjunctivitis cases in the Shanxi province of northern China between 2016 and 2019. Through preliminary identification, virus isolation, and type identification, a total of 63 HAdV isolates were obtained from the samples. Three species and seven types (HAdV-3, HAdV-4, HAdV-8, HAdV-37, HAdV-53, HAdV-64, and HAdV-85) were detected, with HAdV-64, HAdV-3, and HAdV-8 being the predominant types in 2016, 2018, and 2019, respectively. Further phylogenetic analysis indicated the relative genomic stability of seven HAdV-type strains, except for 4 HAdV-3 strains in 2018 with a novel amino acid insertion site (Pro) between P19 and S20 in the penton base gene. It is worth noting that the genomes of two Shanxi HAdV-85 strains from 2016 were almost identical to those of previously reported HAdV-85 strains that circulated in Japan in 2014 to 2018. China was the second country to sample and isolate HAdV-85, suggesting that HAdV-85 might be underreported as an ocular pathogen. Data obtained in this study provide valuable information on the prevalence of acute conjunctivitis caused by HAdV. IMPORTANCE HAdV types in cases of conjunctivitis in Shanxi province, China, in 2016 to 2019 showed evident diversity, with seven types (HAdV-3, HAdV-4, HAdV-8, HAdV-37, HAdV-53, HAdV-64, and HAdV-85) being identified, and relative genome stability of these viruses was observed. In addition, China was the second country to sample and isolate HAdV-85, which suggests that HAdV-85 might be underreported as an important pathogen associated with ocular infections. These results enhance the understanding of the etiology of adenoviral conjunctivitis and may aid in the development of prevention and control strategies for HAdV-related ocular infections in China.

Antiviral Potential of Specially Selected Bulgarian Propolis Extracts: In Vitro Activity against Structurally Different Viruses.

Propolis is a natural mixture of resins, wax, and pollen from plant buds and flowers, enriched with enzymes and bee saliva. It also contains various essential oils, vitamins, mineral salts, trace elements, hormones, and ferments. It has been found that propolis possesses antimicrobial, antiviral, and anti-inflammatory properties. We have studied the antiviral activity of six extracts of Bulgarian propolis collected from six districts of Bulgaria. The study was conducted against structurally different viruses: human coronavirus strain OC-43 (HCoV OC-43) and human respiratory syncytial virus type 2 (HRSV-2) (enveloped RNA viruses), human herpes simplex virus type 1 (HSV-1) (enveloped DNA virus), human rhinovirus type 14 (HRV-14) (non-enveloped RNA virus) and human adenovirus type 5 (HadV-5) (non-enveloped DNA virus). The influence of the extracts on the internal replicative cycle of viruses was determined using the cytopathic effect (CPE) inhibition test. The virucidal activity, its impact on the stage of viral adsorption to the host cell, and its protective effect on healthy cells were evaluated using the final dilution method, making them the focal points of interest. The change in viral infectivity under the action of propolis extracts was compared with untreated controls, and Δlgs were determined. Most propolis samples administered during the viral replicative cycle demonstrated the strongest activity against HCoV OC-43 replication. The influence of propolis extracts on the viability of extracellular virions was expressed to a different degree in the various viruses studied, and the effect was significantly stronger in those with an envelope. Almost all extracts significantly inhibited the adsorption step of the herpes virus and, to a less extent, of the coronavirus to the host cell, and some of them applied before viral infection demonstrated a protective effect on healthy cells. Our results enlarge the knowledge about the action of propolis and could open new perspectives for its application in viral infection treatment.

Metabolic bioprofiling of different Glycyrrhiza glabra solvent fractions for the identification of anti-adenoviral compounds using LC-HRMS/MS and in-vitro cytopathic assay coupled with chemometry

Human adenovirus type-7 (HAdV-7) is a common pathogen that may cause significant morbidity as well as severe complications. Currently, there is no approved drug for the treatment of HAdV-7 infections and the contemporary strategy mainly rely on nonspecific antivirals. Glycyrrhiza glabra; (licorice), is a well-recognized edible plant used in food and beverages. The plant is renowned for its pharmacological and biological activities including antiviral activities against wide range of viruses. The following study reported for the first time the anti-adenoviral activity of licorice extract using in-vitro cytopathic inhibitory assay. Different solvent fractions showed promising activity with IC50 reaching 1.431 μg/ml. Certain fractions had selectivity index (SI) greater than 10 indicating their efficacy together with relatively low cytotoxic effect. Metabolic profiling using LC-HRMS/MS resulted in identification of 41 compounds from licorice fractions. Chemometric modeling using Orthogonal Projections to Latent Structures (OPLS) suggested the compounds; kaempferol-3-O-rutinoside, violanthin, rhamnoliquiritin, isoliquiritigenin isomer, licoagroside B and liquiritin apioside as potential markers against (HAdV-7). Finally, kaempferol-3-O-rutinoside was further confirmed via in-vitro adenovirus inhibitory assay to possess strong antiviral activity with IC50 and CC50 of 54.7 ± 1.93 μM and 655.7 ± 2.22 μM, respectively.

The Metallodrug BOLD-100 Is a Potent Inhibitor of SARS-CoV-2 Replication and Has Broad-Acting Antiviral Activity.

The COVID-19 pandemic has highlighted an urgent need to discover and test new drugs to treat patients. Metal-based drugs are known to interact with DNA and/or a variety of proteins such as enzymes and transcription factors, some of which have been shown to exhibit anticancer and antimicrobial effects. BOLD-100 (sodium trans-[tetrachlorobis(1H-indazole)ruthenate(III)]dihydrate) is a novel ruthenium-based drug currently being evaluated in a Phase 1b/2a clinical trial for the treatment of advanced gastrointestinal cancer. Given that metal-based drugs are known to exhibit antimicrobial activities, we asked if BOLD-100 exhibits antiviral activity towards SARS-CoV-2. We demonstrated that BOLD-100 potently inhibits SARS-CoV-2 replication and cytopathic effects in vitro. An RNA sequencing analysis showed that BOLD-100 inhibits virus-induced transcriptional changes in infected cells. In addition, we showed that the antiviral activity of BOLD-100 is not specific for SARS-CoV-2, but also inhibits the replication of the evolutionarily divergent viruses Human Immunodeficiency Virus type 1 and Human Adenovirus type 5. This study identifies BOLD-100 as a potentially novel broad-acting antiviral drug.

Unexpected Predominance of Human Adenovirus F41 in Children Suffering From Acute Respiratory Infection in Tunisia

Aim: To evaluate human adenovirus (HAdV) types associated with respiratory infections, nasopharyngeal aspirations (NPA) were collected from children under 2 years old that were hospitalized for acute respiratory tract infections (ARTI) during 2018–2019. Methods: PCR was used for viral screening and select samples were then sequenced by Sanger sequencing. Results: Among 194 samples, 30 were HAdV-positive and 14 were chosen for further sequencing. HAdV-F41, C2 and C5 circulated simultaneously with an unexpected predominance of HAdV-F41. HAdV infection occurred year-round, with a peak in winter and early spring. The age group most affected was those younger than 6 months. Conclusion: Continued surveillance of HAdV infections is necessary and the contribution of HAdV-F41 in ARTI should be studied.

Upsurge in hospitalization of pediatric patients with severe acute respiratory infections in Kolkata and surrounding districts caused by recombinant human respiratory adenovirus type B 7/3.

Globally, different genotypes of human adenoviruses are associated with outbreaks of acute respiratory infection (ARI) though such evidence is lacking from India. In the present study, we report a sudden increase in the positivity of respiratory adenovirus among hospitalized children with ARI from Kolkata and the surrounding districts of West Bengal, India, from December 2022 to date. A sharp rise in the positivity rate of respiratory adenovirus was found which ranged from 22.1% in early December 2022 to 52.6% in mid-March 2023. The overall positivity was 40.4% during the period and children in the 2 to <5 years (51.0%) age group were mostly affected. Single infection with adenovirus was found in 72.4% of cases while co-infection with rhinovirus was the maximum (9.4%). Around 97.5% of positive cases required hospitalization. Cough, breathlessness, and wheeze were the most common clinical features among positive patients. Phylogenetic analysis of the hexon and fiber gene of all the sequenced strains revealed HAdV-B 7/3 recombination with more than 99% homology within themselves. This report of a respiratory adenovirus outbreak in West Bengal, India causing severe illness in the pediatric population underscores the need for regular monitoring of the circulating strains.

Differential Genome Replication of a Unique Single-Amino-Acid Mutation in the Adenovirus-4 Component of the Live Oral Adenovirus Type 4 and Type 7 Vaccine.

The FDA-approved Adenovirus Type 4 and Type 7 Vaccine, Live, Oral is highly effective and essential in preventing acute respiratory diseases (ARDs) in U.S. military recruits. Our study revealed the presence of a previously undetected mutation, not found in the wild-type human adenovirus type 4 (HAdV-4) component of the licensed vaccine, which contains an amino acid substitution (P388T) in the pre-terminal protein (pTP). This study demonstrated that replication of the T388 HAdV-4 vaccine mutant virus is favored over the wild type in WI-38 cells, the cell type utilized in vaccine manufacturing. However, results from serial human stool specimens of vaccine recipients support differential genome replication in the gastrointestinal tract (GI), demonstrated by the steady decline of the percentage of mutant T388 vaccine virus. Since vaccine efficacy depends upon GI replication and the subsequent immune response, the mutation can potentially impact vaccine efficacy.

The RNA-binding protein ZC3H11A interacts with the nuclear poly(A)-binding protein PABPN1 and alters polyadenylation of viral transcripts

Nuclear mRNA metabolism is regulated by multiple proteins, which either directly bind to RNA or form multi-protein complexes. The RNA-binding protein ZC3H11A is involved in nuclear mRNA export, NF-κB signaling and is essential during mouse embryo development. Furthermore, previous studies have shown that ZC3H11A is important for nuclear-replicating viruses. However, detailed biochemical characterization of the ZC3H11A protein has been lacking. In this study, we established the ZC3H11A protein interactome in human and mouse cells. We demonstrate that the nuclear poly(A)-binding protein PABPN1 interacts specifically with the ZC3H11A protein and controls ZC3H11A localization into nuclear speckles. We report that ZC3H11A specifically interacts with the human adenovirus type 5 (HAdV-5) capsid mRNA in a PABPN1-dependent manner. Notably, ZC3H11A uses the same zinc finger motifs to interact with PABPN1 and viral mRNA. Further, we demonstrate that the lack of ZC3H11A alters the polyadenylation of HAdV-5 capsid mRNA. Taken together, our results suggest that the ZC3H11A protein may act as a novel regulator of polyadenylation of nuclear mRNA.

Two Novel Adenovirus Vectors Mediated Differential Antibody Responses via Interferon-α and Natural Killer Cells.

Recombinant adenovirus vectors have been widely used in vaccine development. To overcome the preexisting immunity of human adenovirus type 5 (Ad5) in populations, a range of chimpanzee or rare human adenovirus vectors have been generated. However, these novel adenovirus vectors mediate the diverse immune responses in the hosts. In this study, we explored the immune mechanism of differential antibody responses to SARS-CoV-2 S protein in mice immunized by our previously developed two novel simian adenovirus type 23 (Sad23L) and human adenovirus type 49 (Ad49L), and Ad5 vectored COVID-19 vaccines. Sad23L-nCoV-S and Ad5-nCoV-S vaccines induced the low level of interferon-α (IFN-α) and the high level of antigen-specific antibody responses in wild-type and IFN-α/β receptor defective (IFNAR-/-) C57 mice, while Ad49L-nCoV-S vaccine induced the high IFN-α and low antibody responses in C57 mice but the high antibody response in IFNAR-/- mice. In addition, the high antibody response was detected in natural killer (NK) cells-blocked but the low in follicular helper T (TFH) cells -blocked C57 mice immunized with Ad49L-nCoV-S vaccine. These results showed that Ad49L vectored vaccine stimulated IFN-α secretion to activate NK cells, and then reduced the number of TFH cells, generation center (GC) B cells and plasma cells, and subsequently reduced antigen-specific antibody production. The different novel adenovirus vectors could be selected for vaccine development according to the need for either humoral or cellular or both immune protections against a particular disease. IMPORTANCE Novel adenovirus vectors are an important antigen delivery platform for vaccine development. Understanding the immune diversity between different adenoviral vectors is critical to design the proper vaccine against an aim disease. In this study, we described the immune mechanism of Sad23L and Ad49L vectored vaccines for raising the equally high specific T cell response but the different level of specific antibody responses in mice. We found that Ad49L-vectored vaccine initiated the high IFN-α and activated NK cells to inhibit antibody response via downregulating the number of CD4+ TFH cells leading to the decline of GC B cells and plasma cells.