Human Adenovirus Type Research Articles

Reverse resistance to immune checkpoint inhibitor in a patient with recurrent cardia cancer by intratumoral injection of recombinant human adenovirus type 5: a case report and literature review

Advanced metastatic cardia cancer is an intractable malignance with poor prognosis. It is often accompanied by upper digestive tract obstruction, which seriously affects the quality of patients. Therefore, effective relief of eating obstruction is an important goal in the treatment of cardia cancer. Immune checkpoint inhibitors (ICIs) have shown significant efficacy in cardia cancer, but only a small percentage of patients will benefit from them due to immune resistance. Oncolytic viruses have been shown to enhance the efficacy of ICIs by altering the immune microenvironment. This indicates that oncolytic virus has the potential value of overcoming the immune resistance of cardia cancer. Here, we present a case with local recurrent and multiple metastatic cardia cancer accompanied by eating obstruction. After 4 cycles of chemotherapy plus ICI therapy, the patient´s metastases were significant shrink, but the recurrent carida lesion were almost unchanged. Then we implemented exploratory local injection of recombinant human adenovirus type 5(H101) into recurrent cardia lesion by painless gastroscopy. Surprisingly, the cardia lesion shrank significantly, and the eating obstruction was greatly relieved. We also observed a significant increase of infiltrated CD4+T cells in biopsy tissues after H101 treatment. Our study not only conformed the value of oncolytic viruses to reverse ICI resistance in patients with gastric cancer, but also revealed its underlying impact on immune microenvironment.

Longitudinal Analysis of Binding Antibody Levels Against 39 Human Adenovirus Types in Sera from 60 Regular Blood Donors from Greifswald, Germany, over 5 Years from 2018 to 2022

Adenoviruses are important human pathogens that are widespread and mainly associated with respiratory and gastrointestinal infections. In a previous study on human adenovirus (HAdV) seroprevalence, we observed reduced binding antibody levels against a range of HAdV types in sera collected from students in 2021 compared to sera collected before the SARS-CoV-2 pandemic. In this follow-up study, we wanted to verify this observation in a cohort of regular blood donors for whom serial samples were available. Therefore, HAdV-specific binding antibody levels were analyzed in sera collected over a 5-year period from 2018 to 2022 in a cohort of 60 regular donors to the blood bank of the University Hospital in Greifswald, Germany. Using ELISA-based assays, we quantified the binding antibody responses against 39 HAdV types. On the cohort level, we found largely stable antibody levels over the analyzed time period, with the highest antibody responses against HAdV-C1, -D25, -D26, -E4, -D10, -D27, -C5, -D75, -C2, and -C6. Only minor but significant reductions in comparison to the first serum samples from 2018 were detected for antibody levels in 2021 and 2022 against the low-prevalent types HAdV-A31, -D8, -D20, -D37, -D65, and -D69. On the other hand, we detected fluctuations in antibody levels on the individual level, with strong increases in antibody levels indicative of novel antigen contact. Interestingly, we frequently found simultaneous changes in antibody responses against multiple HAdV types, resulting in strong correlations of antibody responses against distinct clusters of HAdVs suggesting extensive cross-reactivity of HAdV-specific antibodies. To our knowledge, this is the first study of antibodies against a broad range of HAdV types in serum samples collected from a cohort of individuals over a prolonged period, and our data provide important insight into the long-term stability of HAdV-specific antibody levels. In this cohort of regular blood donors, we did not observe any major impact of the SARS-CoV-2 pandemic on HAdV immunity. Correlations of changes in antibody levels against different types indicate cross-reactivity of HAdV-specific antibodies that are important to consider for HAdV vector development. Our data also reveal possible candidates for future development of HAdV-based vectors.

Construction and validation of a mouse model for studying severe human adenovirus infections

Human adenoviruses (HAdVs) are highly contagious pathogens with various genotypes implicated in acute respiratory disease (ARD) and linked to mortality, especially in immunosuppressed patients, young children, and military recruits. Currently, no vaccines or specific drugs are approved for clinical use. The hosts of adenoviruses are strictly species-specific, which strongly limits the development of vaccines and drugs against HAdVs. In this study, immunocompetent BALB/c mice were challenged with different doses of human adenovirus type 5 (HAdV-5) via tail intravenous injection (i.v.). All mice challenged with a high dose of HAdV-5 (3.2×1010 TCID50/kg) died within 3 to 5 days, while those receiving a low dose of HAdV-5 (8×109 or 4×109 TCID50/kg) survived. Interestingly, among the mice receiving a medium dose of HAdV-5 (1.6×1010 TCID50/kg), 60% (n = 3/5) of male mice died, while all female mice survived. This suggests that male mice may be more susceptible to HAdV-5 infection than female mice, consistent with clinical findings in children. HAdV-5 DNA was mainly distributed in the liver, followed by the spleen and lungs. Pathological changes were observed in the lungs, liver, and spleen, with severity increasing in correlation with the virus challenge dosage. Transcriptome and qPCR analyses of the liver indicated that the down-regulated expression of the H2-Aa, H2-Ea-ps, CD74, and H2-Eb1 genes in male mice, as well as the AHR gene in female mice, may contribute to the observed higher mortality rates in male mice. Therefore, this effective, feasible, and cost-efficient mouse model could serve as a candidate for evaluating HAdV vaccines and anti-adenovirus therapeutics.

Metabolomic Profiling Reveals New Insights Into Human Adenovirus Type 7 Infection

Human adenovirus type 7 (HAdV-7) is a prominent pathogen that causes severe pneumonia in children in China. However, the interaction between HAdV-7 infection and host metabolism is still poorly understood. To gain a comprehensive understanding of the metabolic interplay between host cells and the virus, we analysed the energy and lipid metabolism profiles of the HAdV-7-infected lung cancer cell line A549 by ultrahigh-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (ESI-QTRAP-MS/MS). Our study revealed significant alterations in various metabolic processes, including the tricarboxylic acid cycle, purine and pyrimidine metabolism, amino acid metabolism, nucleotide metabolism, and lipid metabolism, in A549 cells after HAdV-7 infection. Moreover, HAdV-7 infection stimulated enhanced synthesis of membrane lipids in A549 cells. These findings emphasize the crucial role of metabolism in viral infection and suggest that modulating host cell metabolism could be a promising approach for targeted drug development and infection control.

A newly identified secretory phospholipase A2 group XIIA homolog (LcPLA2XIIA) in Larimichthys crocea exhibits antimicrobial and antitumor activities

The phospholipase A2 (PLA2) superfamily has attracted increasing attention in recent years due to the multiple physiological and pathological functions exerted by its members. Up to date, the knowledge about the biological role of PLA2XIIA subfamily members remains limited. In this study, a new member of PLA2XIIA subfamily, LcPLA2XIIA, was characterized in large yellow croaker. Different from most members of the PLA2 superfamily with positive charge, LcPLA2XIIA encodes an anionic protein, which is similar to other members of PLA2XIIA subfamily. LcPLA2XIIA is highly expressed in the intestine, and afterwards, it is up-regulated after with Pseudomonas plecoglossicida or Staphylococcus aureus. LcPLA2XIIA exhibits strong inhibitory activity against these two bacteria. The results indicate that LcPLA2XIIA plays an important role in the antimicrobial immune responses of large yellow croaker. LcPLA2XIIA displays strong binding activity to all the tested bacteria. It specifically interacts with LTA, a unique component on the surface of Gram-positive bacteria. It also significantly promotes bacterial agglutination in the presence of Ca2+. These findings reveal that the binding and agglutinating abilities of LcPLA2XIIA to bacteria contribute greatly to its antibacterial activity. In addition, LcPLA2XIIA significantly inhibits the proliferation of infectious hematopoietic necrosis virus instead of recombinant human adenovirus type 5. It also suppresses the growth of human colorectal adenocarcinoma cells by inducing apoptosis, but it has no obvious inhibitory effect on the growth of epithelioma papulosum cyprinid cells. This study provides new insights into the antibacterial activity, and the mechanism of LcPLA2XIIA in large yellow croaker, and antiviral and antitumor functions of PLA2XIIA subfamily members.

Adenovirus-5 and adenovirus-37 seropositivity in obese patients

Background and Objectives: Obesity is a major health issue linked to conditions like diabetes, hypertension, and hy- perlipidemia. Infectobesity suggests that certain microorganisms may contribute to obesity. Human adenovirus serotypes, particularly Human adenovirus type-36 (HAdV-36), Human adenovirus type-5 (HAdV-5), and Human adenovirus type-37 (HAdV-37), are thought to influence body fat regulation. This study investigates the relationship between Immunoglobulin G (IgG) positivity for HAdV-5 and HAdV-37 and obesity, aiming to provide data on the infectious etiology of obesity. Materials and Methods: Blood samples separated into serums from obese (BMI ≥30) and non-obese (BMI 18.5-25) indi- viduals were tested for HAdV-5 and HAdV-37 seropositivity using ELISA kits and seropositivity rates between the groups were compared. Results: HAdV-37 antibody positivity was significantly higher in obese patients (39/48) compared to the control group (24/42) (p=0.011). For HAdV-5, antibody positivity was similar in both groups (26 individuals each) with no significant difference (p=0.461). No significant gender-related differences were found for either serotype. Conclusion: The study suggests HAdV-37 may be associated with obesity, while no such relationship was found for HAdV- There was no gender association for either serotype. These results align with existing literature on HAdV-37, but further research is needed to confirm the link between adenoviruses and obesity and explore potential treatment options.

Molecular characterization of human adenovirus associated with pediatric severe acute respiratory infections in a tertiary care hospital in North East India

PurposeThe present study explored the molecular characterization of human Adenovirus (HAdV) and its strains among hospitalized SARI cases in the pediatric unit of a tertiary care hospital in North-East India.MethodsNasal and throat swabs were collected from 70 patients of Pediatric Unit, of a tertiary hospital in NE India from April 2023-October 2023. The samples were screened for the presence of HAdV using an adenovirus-specific Real-Time PCR Kit. For molecular characterization, Next Generation Sequencing (NGS) was performed by targeting the hexon gene of HAdV followed by post-sequencing analysis.ResultsOverall, 18.57% (13/70) of samples were positive for HAdV. In context of the severity of illness, 3/13 adenovirus-positive patients (23.07%) died after hospitalization, had severe pneumonia among which two were of less than one year of age. Molecular characterization using NGS indicated that 4/13 individuals were infected with HAdV-B type 3 and 5/13 patients were infected with HAdV type 7. Notably, 4/7 cases of severe pneumonia were under five years of age and associated with HAdV type 7 infection. The ratio of non-synonymous to synonymous mutation (dN/dS) was comparatively low in HAdV type 7 positive samples (dN/dS=0.31). No non-synonymous mutation was observed in HAdV-B type 3 positive samples. The higher neutrophil percentage among the death cases suggested an acute immune response.ConclusionThe study demonstrated HAdV type 7 and HAdV-B type 3 as strains associated with pediatric SARI cases from April 2023-October 2023. Further, HAdV type 7 infection was primarily linked with lower respiratory tract infections mainly severe pneumonia.

Immunogenicity of various variants of Ebola and Marburg virus glycoprotein genes in recombinant adenoviral vectors

INTRODUCTION. Marburg and Ebola viruses cause severe haemorrhagic fever in humans and primates. Currently, there are no licensed prophylactic vaccines that can simultaneously prevent the spread or reduce the severity of both diseases caused by these filoviruses. The development of effective prophylactic vaccines requires studies aimed at selecting the most immunogenic forms of protective antigens.AIM. This study aimed to evaluate humoral immune induction in animals after administration of recombinant adenoviral vectors expressing various forms of Ebola and Marburg virus glycoproteins (GPs).MATERIALS AND METHODS. Samples of recombinant human adenovirus type 5 (rAd5) were obtained using homologous recombination in Escherichia coli, growth in HEK293 cells, and purification by CsCl gradient ultracentrifugation. The resulting rAd5 samples were characterised in terms of their identity (PCR and whole-genome sequencing), the concentration of viral particles (fluorescence spectroscopy), and the concentration of infectious viral particles (TCID50 assay). Enzyme-linked immunosorbent assay (ELISA) was used to evaluate the GP-specific IgG titres in the sera of immunised mice.RESULTS. The authors constructed rAd5 samples, and each construct contained an expression cassette with a GP gene form encoding a full-length GP, a GP without the mucin-like domain, or a GP without both the glycan cap and the mucin-like domain. Each of these forms was studied using the GPs of four filoviruses, including Zaire Ebola virus, Sudan Ebola virus, Bundibugyo Ebola virus, and Marburg virus. Neither of the forms had a critical effect on the rAd5 replicative capacity. Three weeks after immunisation, the highest GP-specific IgG production was induced by the rAd5 samples encoding either the full-length GP or the GP without the mucin-like domain. The GP without both the glycan cap and the mucin-like domain was the least immunogenic antigen regardless of the filovirus species.CONCLUSIONS. The most promising constructs for the development of filovirus vaccines based on recombinant adenoviral vectors are the constructs that include the genes encoding the fulllength GP or the GP without the mucin-like domain.

Outbreak of severe acute respiratory infections caused by recombinant human adenovirus type B 7/3 in hospitalized infants from a nursery in Dakar, April 2024

ObjectivesAcute respiratory infections are among the leading cause of mortality in children under 5 years of age worldwide, with most of these deaths due to bronchiolitis and pneumonia. We investigated and analyzed a pediatric outbreak of acute respiratory infections that resulted in the hospitalization of four infants in a nursery in Dakar in late April 2024. MethodsNasopharyngeal specimens were collected from infants and tested for a panel of respiratory pathogens by multiplex real-time reverse transcription–polymerase chain reaction. Subsequently, the positive samples underwent next-generation sequencing for molecular analysis. ResultsHuman adenovirus (HAdV) was the principal etiologic agent detected in hospitalized infants with pneumonia and nearly half (46.7%; seven of 15) of the suspected cases identified during the investigation at the nursery. All the HAdV isolates were classified as being of subgroup B1. Molecular characterization revealed that infants attending the nursery were infected with a recombinant HAdV strain containing an adenovirus serotype 7 penton and serotype 3 hexon and fiber proteins. ConclusionsOur findings reinforce previous evidence that recombination leads to the emergence of new adenovirus strains with epidemic and lethal potential. These results emphasize the need to strengthen surveillance in inpatient settings across the country.

Prevalence of Human Adenovirus Type 3 Associated with Pharyngoconjunctival Fever in Children in Osaka, Japan during and after the COVID-19 Pandemic.

The incidence and type distribution of human adenovirus (HAdV) infections among children with pharyngoconjunctival fever (PCF) in Osaka, Japan between 2019 and 2023 were analyzed to assess the effect of the coronavirus disease 2019 (COVID-19) pandemic. The number of reported PCF cases in Osaka decreased from 2020 to 2022, followed by an unprecedented increase in 2023. HAdV-C strains, including types C1, C2, and C5, were detected in throughout the study period. Conversely, HAdV-B3 was not detected for 2 years and 9 months from March 2020 to December 2022, but the number of detections increased from July 2023. Overall, HAdV-B3 was the most frequently detected type (27 of 52 strains), and genetic analysis of its hexon hypervariable regions showed that, except for one strain, the HAdV-B3 strains identified after 2022 had different amino acid substitutions to those identified in 2019 and 2020. These results suggest that the PCF epidemic in 2023 was predominantly caused by variant strains of HAdV-B3, and that children were susceptible owing to a lack of exposure to HAdV-B3 between 2020 and 2022. Ongoing surveillance is needed to evaluate the impact of COVID-19 on the prevalence of HAdV infection.

Prime-boost immunization with inactivated human adenovirus type 55 combined with an adjuvant enhances neutralizing antibody responses in mice

BackgroundHuman adenovirus type 55 (hAd55) infection can lead to acute respiratory diseases that often present with severe symptoms. Despite its persistent prevalence in military camps and communities, there are no commercially available vaccines or vaccine candidates undergoing clinical evaluation; therefore, there is an urgent need to address this. In this study, we evaluated the immunogenicity of inactivated hAd55 isolates and investigated the effects of adjuvants and various immunization intervals.Methods and resultsTo select a vaccine candidate, four hAd55 strains (6–9, 6–15 (AFMRI 41014), 28–48 (AFMRI 41013), and 12–164 (AFMRI 41012)) were isolated from infected patients in military camps. Sequence analysis revealed no variation in the coding regions of structural proteins, including pentons, hexons, and fibers. Immunization with inactivated hAd55 isolates elicited robust hAd55-specific binding and neutralizing antibody responses in mice, with adjuvants, particularly alum hydroxide (AH), enhancing antibody titers. Co-immunization with AH also induced hAd14-specific neutralizing antibody responses but did not induce hAd11-specific neutralizing antibody responses. Notably, booster immunization administered at a four-week interval resulted in superior immune responses compared with shorter immunization intervals.ConclusionsPrime-boost immunization with the inactivated hAd55 isolate and an AH adjuvant shows promise as a potential approach for preventing hAd55-induced respiratory disease. Further research is needed to evaluate the efficacy and safety of these vaccine candidates in preventing hAd55-associated respiratory illnesses.

Human adenovirus type 4 (HAdV-4) associated acute respiratory tract infection in children & genetic characteristics of HAdV-4 in China: a prospective multicenter study

BackgroundHuman adenovirus (HAdV) is an important pathogen causing acute respiratory infection (ARI) in children. Many countries, including China, have experienced sporadic or outbreaks related to HAdV-4, and death cases were reported. However, there is little research on HAdV-4 and the epidemic situation of HAdV-4 in China is little known. This study was designed to comprehend the prevalence and genetic characteristics of HAdV-4 in ARI children in China.MethodsRespiratory tract samples from ARI children hospitalized in six hospitals of Northern and Southern China from 2017 to 2020 were collected for HAdV detection and typing. Clinical information was collected from HAdV-4 positive patients for clinical characteristics and epidemiological analysis. The main capsid proteins and the whole genome sequences were amplified and sequenced for bioinformatics analysis.ResultsThere were 2847 ARI children enrolled, and 156 (5.48%) HAdV positive samples were detected. Eleven HAdV-4 positive samples were identified, accounting for 0.39% of the total samples and 7.05% of the HAdV positive samples. The main manifestations were fever and cough. Two children had conjunctivitis. Two children were diagnosed with severe pneumonia and developed respiratory failure. One of them developed hemophagocytic syndrome and checked in pediatric intensive care unit (PICU). This child had ventricular septal defect. All the children recovered. The isolated strains of HAdV-4 obtained in this study and the reference strains from China located in the same phylogenetic branch (HAdV-4a), while the prototype strain and vaccine strains formed another branch (HAdV-4p). Upon comparison with the prototype strain, there were a few amino acid mutations existing in three major capsid proteins. According to recombination analysis, no new recombination was found.ConclusionsThe detection rate of HAdV-4 in children hospitalized with ARI was 0.39% in the total samples and 7.05% of all HAdV positive samples. HAdV-4 isolates obtained in this study and other reference strains from China belonged to the HAdV-4a subtype. Our data provided reference for the monitoring, prevention and control of HAdV-4, as well as the research and development of vaccines and drugs.

Multispecies Cocirculation of Adenoviruses Identified by Next-Generation Sequencing During an Acute Gastroenteritis Outbreak in Coastal Kenya in 2023.

Although 7 human adenovirus (HAdV) species are known to exist, only F (types 40 and 41) and G are identified as diarrheal disease agents. The role of other HAdV species in diarrheal disease remains unclear, and data on their prevalence are limited. We describe HAdV species and types in hospitalized children with diarrhea in coastal Kenya. Three hundred twenty-nine stool samples collected between June 2022 and August 2023 from children aged <13 years were screened for HAdV using quantitative polymerase chain reaction (qPCR). Positive HAdV cases were genotyped by adenovirus primers from the RespiCoV panel by amplification, next-generation sequencing, and phylogenetic analysis. Sixty-five samples (20%) tested HadV positive, of which 5 HAdV species were identified. Other than HAdV F, other species included A, B, C, and D; these were detected as either mono-detections or coinfections. Six HAdV F identified by NGS had been missed by our qPCR typing method. This appeared to be as a result of a 133-nucleotide deletion in the long fiber protein, which abrogated a primer and probe binding site. Based on grading of diarrheal disease severity using VESIKARI scores, 93% of the HAdV cases presented with severe disease. One child with an HAdV F infection died. Our study shows the enormous diversity and clinical characteristics of HAdV species in children with diarrhea in coastal Kenya. These data offer an opportunity to improve current diagnostic assays and increase knowledge of HAdV in Africa for control of outbreaks in the future.

3D‐Printed Highly Porous Functional Materials for the Efficient Removal of Adenovirus

AbstractHierarchical porous acrylate‐based materials are highly interesting as 3D filter materials, such as for virus removal from suspensions. Here, the synthesis of highly porous monolithic 3D materials by polymerization‐induced phase separation in liquid crystal display (LCD) based 3D printing is presented for the efficient removal of human adenovirus type 5. The hierarchical porosity can be tuned via the variation of the photocurable resin composition (i.e., inherent porosity) and the computer‐aided design (i.e., “printed” porosity; microchannels). 3D polymer structures with highly intricate geometries and structural features ranging from ≈20 nm up to cm can be achieved, which can be used for effective virus removal in a laboratory‐scale flow‐through approach. Combined focused ion beam/scanning electron microscopy tomography and mercury porosimetry provide detailed information on the inherent pore size, pore size distribution, and pore interconnectivity, which is key for the performance of such functional 3D materials. Polymers with a theoretical void volume of 75% show virus capture with a removal efficiency of ≈70% of the adenovirus. Polymers with the same theoretical void volume and macroscopic design but a more hydrophobic nature captured only ≈33%. An optimized adenovirus retention of 98% is achieved by adjusting the microchannels of the tunable inserts.

Elimination of Human Papillomavirus 16-Positive Tumors by a Mucosal rAd5 Therapeutic Vaccination in a Pre-Clinical Murine Study.

Therapeutic vaccination can harness the body's cellular immune system to target and destroy cancerous cells. Several treatment options are available to eliminate pre-cancerous and cancerous lesions caused by human papillomaviruses (HPV), but may not result in a long-term cure. Therapeutic vaccination may offer an effective, durable, and minimally intrusive alternative. We developed mucosally delivered, recombinant, non-replicating human adenovirus type 5 (rAd5)-vectored vaccines that encode HPV16's oncogenic proteins E6 and E7 alongside a molecular dsRNA adjuvant. The induction of antigen-specific T cells and the therapeutic efficacy of rAd5 were evaluated in a mouse model of HPV tumorigenesis where E6E7-transformed cells, TC-1, were implanted subcutaneously in C57BL/6 mice. After tumor growth, mice were treated intranasally with rAd5 vaccines expressing the wildtype form of E6E7 (rAd5-16/E6E7Wt) in combination with an anti-PD-1 antibody or isotype control. Animals treated with rAd5-16/E6E7Wt with and without anti-PD-1 had significant reductions in tumor volume and increased survival compared to controls. Further, animals treated with rAd5-16/E6E7Wt had increased CD4+ and CD8+ tumor-infiltrating lymphocytes (TILs) and produced a cytotoxic tumor microenvironment. In a second study, the immunogenicity of a non-transformative form of E6E7 (rAd5-16/E6E7Mu) and a vaccine encoding predicted T cell epitopes of E6E7 (rAd5-16/E6E7epi) were evaluated. These vaccines elicited significant reductions in TC-1 tumor volume and increased survival of animals. Antigen-specific CD8+ T effector memory cells were observed in the animals treated with E6E7-encoding rAd5, but not in the rAd5-empty group. The work described here demonstrates that this mucosal vaccination can be used therapeutically to elicit specific cellular immunity and further identifies a clinical candidate with great potential for the treatment and prevention of human cervical cancer.

The short fiber knobs of human adenovirus in species F elicit cross-neutralizing antibody responses

Human adenovirus (HAdV) type 40 in species F (HAdV-F40) and HAdV-F41 represent the third most prevalent causative agents of non-bacterial acute gastroenteritis in infants and young children, following norovirus and rotavirus. Despite their significant contribution to global child morbidity, vaccines to preemptively combat these viruses remain elusive. In this study, we investigate the potential for cross-neutralization between HAdV-F40 and HAdV-F41 using immune sera with the short fiber knob (SFK). We implemented a series of assays to evaluate the responses, including enzyme-linked immunosorbent, micro-neutralization, immunofluorescence, and quantitative polymerase chain reaction. Our results demonstrate that immune sera with HAdV-F40 SFK or HAdV-F41 SFK could effectively neutralize both HAdV-F40 and HAdV-F41, indicating a mutual cross-neutralizing effect. Notably, the immune sera with HAdV-F40 SFK demonstrated a stronger neutralization effect, suggesting the potential to develop a subunit vaccine that can simultaneously counteract both viruses. These findings underscore the potential of SFK immunization in evoking a cross-neutralizing antibody response between HAdV-F40 and HAdV-F41. This suggests a promising avenue for developing subunit vaccines against HAdV-F40 and HAdV-F41 and provides a novel perspective on the potential of neutralizing antibodies to protect against these two types of HAdV.

Development and implementation of assays to monitor human adenovirus F40/41 in wastewater: Trends preceding, during, and following the non-A-to-E hepatitis outbreak in Stockholm

Human adenovirus (HAdV) type F41 has been identified as a possible cause of the non-A-to-E hepatitis outbreak. This study uses wastewater monitoring to track HAdV F40 and F41, supporting clinical investigations and providing insights into the pathogen’s role in the outbreak. Given the limited clinical monitoring in Sweden of HAdV-F40/41, this approach also helps estimate the true infection burden of this pathogen during the outbreak.This study developed three qPCR assays for the hexon, penton, and fiber genes of HAdV F40 and F41. The hexon assay was F41-specific, while the fiber assay detected multiple HAdV-F strains. Comprehensive monitoring of HAdV-F40/41 levels in Stockholm’s wastewater was conducted over 1.5 years, capturing the period before, during, and after the outbreak. A significant infection wave was observed in spring 2022, with strains beyond lineage 2 contributing to the outbreak. Moreover, simultaneous SARS-CoV-2 surveillance revealed that HAdV-F infections peaked at different times from COVID-19, but the HAdV-F wave aligned with the relaxation of pandemic restrictions. These findings offer valuable insights for future HAdV-F investigations and confirm its role in the non-A-to-E hepatitis outbreak.

Inhibition of B cell receptor signaling induced by the human adenovirus species D E3/49K protein.

The early transcription unit 3 (E3) of human adenoviruses (HAdVs) encodes several immunoevasins, including the E3/49K protein, which is unique for species D of HAdVs. It is expressed as surface transmembrane protein and shed. E3/49K of HAdV-D64 binds to the protein tyrosine phosphatase surface receptor CD45, thereby modulating activation of T and NK cells. Considering that E3/49K represents the most polymorphic viral protein among species D HAdVs, we demonstrate here that all tested E3/49K orthologs bind to the immunologically important regulator CD45. Thus, this feature is conserved regardless of the pathological associations of the respective HAdV types. It appeared that modulation of CD45 is a unique property restricted to HAdVs of species D. Moreover, E3/49K treatment inhibited B cell receptor (BCR) signaling and impaired BCR signal phenotypes. The latter were highly comparable to B cells having defects in the expression of CD45, suggesting E3/49K as a potential tool to investigate CD45 specific functions. We identified B cells as new direct target of E3/49K-mediated immune modulation, representing a novel viral immunosubversive mechanism.

Recombinant human adenovirus type 5 promotes anti-tumor immunity via inducing pyroptosis in tumor endothelial cells.

Recombinant human type 5 adenovirus (H101) is an oncolytic virus used to treat nasopharyngeal carcinoma. Owing to the deletion of the E1B-55kD and E3 regions, H101 is believed to selectively inhibit nasopharyngeal carcinoma. Whether H101 inhibits other type of tumors via different mechanisms remains unclear. In this study we investigated the effects of H101 on melanomas. We established B16F10 melanoma xenograft mouse model, and treated the mice with H101 (1 × 108 TCID50) via intratumoral injection for five consecutive days. We found that H101 treatment significantly inhibited B16F10 melanoma growth in the mice. H101 treatment significantly increased the infiltration of CD8+ T cells and reduced the proportion of M2-type macrophages. We demonstrated that H101 exhibited low cytotoxicity against B16F10 cells, but the endothelial cells were more sensitive to H101 treatment. H101 induced endothelial cell pyroptosis in a caspase-1/GSDMD-dependent manner. Furthermore, we showed that the combination of H101 with the immune checkpoint inhibitor PD-L1 antibody (10 mg/kg, i.p., every three days for three times) exerted synergic suppression on B16F10 tumor growth in the mice. This study demonstrates that, in addition to oncolysis, H101 inhibits melanoma growth by promoting anti-tumor immunity and inducing pyroptosis of vascular endothelial cells.

A significant outbreak of respiratory human adenovirus infections among children aged 3-6 years in Hokkaido, Japan, in 2023.

Human adenovirus (HAdV) infections present diverse clinical manifestations upon infecting individuals, with respiratory infections predominating in children. We surveyed pediatric hospitalizations due to respiratory HAdV infections across 18 hospitals in Hokkaido Prefecture, Japan, from July 2019 to March 2024, recording 473 admissions. While hospitalizations remained below five cases per week from July 2019 to September 2023, a notable surge occurred in late October 2023, with weekly admissions peaking at 15-20 cases from November to December. There were dramatic shifts in the age distribution of hospitalized patients: during 2019-2021, 1-year-old infants and children aged 3-6 years represented 51.4%-54.8% and 4.1%-13.3%, respectively; however, in 2023-2024, while 1-year-old infants represented 19.0%-20.1%, the proportion of children aged 3-6 years increased to 46.2%-50.0%. Understanding the emergence of significant outbreaks of respiratory HAdV infections and the substantial changes in the age distribution of hospitalized cases necessitates further investigation into the circulating types of HAdV in Hokkaido Prefecture and changes in children's neutralizing antibody titers against HAdV.