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Nature May 2023An outbreak of acute hepatitis of unknown aetiology in children was reported in Scotland in April 2022 and has now been identified in 35 countries. Several recent...
An outbreak of acute hepatitis of unknown aetiology in children was reported in Scotland in April 2022 and has now been identified in 35 countries. Several recent studies have suggested an association with human adenovirus with this outbreak, a virus not commonly associated with hepatitis. Here we report a detailed case-control investigation and find an association between adeno-associated virus 2 (AAV2) infection and host genetics in disease susceptibility. Using next-generation sequencing, PCR with reverse transcription, serology and in situ hybridization, we detected recent infection with AAV2 in plasma and liver samples in 26 out of 32 (81%) cases of hepatitis compared with 5 out of 74 (7%) of samples from unaffected individuals. Furthermore, AAV2 was detected within ballooned hepatocytes alongside a prominent T cell infiltrate in liver biopsy samples. In keeping with a CD4 T-cell-mediated immune pathology, the human leukocyte antigen (HLA) class II HLA-DRB1*04:01 allele was identified in 25 out of 27 cases (93%) compared with a background frequency of 10 out of 64 (16%; P = 5.49 × 10). In summary, we report an outbreak of acute paediatric hepatitis associated with AAV2 infection (most likely acquired as a co-infection with human adenovirus that is usually required as a 'helper virus' to support AAV2 replication) and disease susceptibility related to HLA class II status.
Topics: Child; Humans; Acute Disease; Adenovirus Infections, Human; Alleles; Case-Control Studies; CD4-Positive T-Lymphocytes; Coinfection; Dependovirus; Genetic Predisposition to Disease; Helper Viruses; Hepatitis; Hepatocytes; HLA-DRB1 Chains; Liver
PubMed: 36996873
DOI: 10.1038/s41586-023-05948-2 -
Oncoimmunology 2022Resistance remains an obstacle to anti-programmed cell death protein 1 (PD-1) therapy in human cancer. One critical resistance mechanism is the lack of T cell chemotaxis...
Resistance remains an obstacle to anti-programmed cell death protein 1 (PD-1) therapy in human cancer. One critical resistance mechanism is the lack of T cell chemotaxis in the tumor microenvironment (TME). CXCL10-CXCR3 signaling is required for T cell tumor infiltration and tumor immunotherapy. Oncolytic viruses (OVs), including oncolytic adenoviruses (AdVs), induce effective T cell immunity and tumor infiltration. Thus, arming OV with CXCL10 would be an attractive strategy to overcome resistance to anti-PD1 therapy. Here, we successfully constructed a novel recombinant oncolytic adenovirus encoding murine CXCL10, named Adv-CXCL10. Through intratumoural injection, the continuous expression of the functional chemokine CXCL10 in the TME is realized to recruit more CXCR3 T cells into the TME to kill tumor cells, and the recombinant adenovirus shows great power to 'fire up' the TME and enhance the antitumour efficiency of PD-1 antibodies.
Topics: Adenoviridae; Adenoviridae Infections; Animals; Chemokine CXCL10; Chemotaxis; Humans; Mice; Neoplasms; Oncolytic Viruses; Rhabdomyosarcoma, Alveolar; Tumor Microenvironment
PubMed: 36092638
DOI: 10.1080/2162402X.2022.2118210 -
FEBS Letters Jun 2020Both well-known and emerging viruses increasingly affect humans and cause disease, sometimes with devastating impact on society. The viruses present in the biosphere are...
Both well-known and emerging viruses increasingly affect humans and cause disease, sometimes with devastating impact on society. The viruses present in the biosphere are the top predators in the life chain, virtually without enemies, except perhaps the immune system, and harsh environmental physicochemical conditions restricting their dissemination. We know a lot about viruses, but do we know enough? This series of reviews is dedicated to adenoviruses (AdVs), a family of nonenveloped DNA viruses occurring in vertebrates, including humans. AdVs have been the focus of intense research for more than 67 years. Besides causing disease, they have immensely contributed to the advance of life sciences and medicine over the past decades. Recently, AdVs have been widely used as vehicles in gene therapy and vaccination. They continue to provide fundamental insights into virus-host interactions in cells, tissues and organisms, as well as systems and metabolic networks. This special issue of FEBS Letters presents a unique collection of 23 state-of-the-art review articles by leading adenovirologists. In this prelude, I present the chapters, which provide a solid basis for further exploring the rich heritage in adenovirus molecular cell biology, structural biology, genetics, immunology, gene therapy and epidemiology. I conclude with an essential discussion of six blind spots in adenovirology.
Topics: Adenoviridae; Adenoviridae Infections; Animals; Host-Pathogen Interactions; Humans; Virus Internalization
PubMed: 32538496
DOI: 10.1002/1873-3468.13849 -
PLoS Pathogens Nov 2020Enteric alpha-defensins are potent effectors of innate immunity that are abundantly expressed in the small intestine. Certain enteric bacteria and viruses are resistant...
Enteric alpha-defensins are potent effectors of innate immunity that are abundantly expressed in the small intestine. Certain enteric bacteria and viruses are resistant to defensins and even appropriate them to enhance infection despite neutralization of closely related microbes. We therefore hypothesized that defensins impose selective pressure during fecal-oral transmission. Upon passaging a defensin-sensitive serotype of adenovirus in the presence of a human defensin, mutations in the major capsid protein hexon accumulated. In contrast, prior studies identified the vertex proteins as important determinants of defensin antiviral activity. Infection and biochemical assays suggest that a balance between increased cell binding and a downstream block in intracellular trafficking mediated by defensin interactions with all of the major capsid proteins dictates the outcome of infection. These results extensively revise our understanding of the interplay between defensins and non-enveloped viruses. Furthermore, they provide a feasible rationale for defensins shaping viral evolution, resulting in differences in infection phenotypes of closely related viruses.
Topics: A549 Cells; Adenoviridae; Adenoviridae Infections; Antiviral Agents; Capsid Proteins; Evolution, Molecular; Humans; Immunity, Innate; Intestine, Small; Models, Molecular; Mutation; Serogroup; alpha-Defensins
PubMed: 33232373
DOI: 10.1371/journal.ppat.1009018 -
Nature May 2023Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK....
Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children.
Topics: Child; Humans; Acute Disease; Adenovirus Infections, Human; B-Lymphocytes; Gene Expression Profiling; Genomics; Hepatitis; Immunohistochemistry; Liver; Proteomics; T-Lymphocytes
PubMed: 36996872
DOI: 10.1038/s41586-023-06003-w -
Viruses Apr 2022The expression of cytokines and chemokines in response to adenovirus infection is tightly regulated by the innate immune system. Cytokine-mediated toxicity and cytokine... (Review)
Review
The expression of cytokines and chemokines in response to adenovirus infection is tightly regulated by the innate immune system. Cytokine-mediated toxicity and cytokine storm are known clinical phenomena observed following naturally disseminated adenovirus infection in immunocompromised hosts as well as when extremely high doses of adenovirus vectors are injected intravenously. This dose-dependent, cytokine-mediated toxicity compromises the safety of adenovirus-based vectors and represents a critical problem, limiting their utility for gene therapy applications and the therapy of disseminated cancer, where intravenous injection of adenovirus vectors may provide therapeutic benefits. The mechanisms triggering severe cytokine response are not sufficiently understood, prompting efforts to further investigate this phenomenon, especially in clinically relevant settings. In this review, we summarize the current knowledge on cytokine and chemokine activation in response to adenovirus- and adenovirus-based vectors and discuss the underlying mechanisms that may trigger acute cytokine storm syndrome. First, we review profiles of cytokines and chemokines that are activated in response to adenovirus infection initiated via different routes. Second, we discuss the molecular mechanisms that lead to cytokine and chemokine transcriptional activation. We further highlight how immune cell types in different organs contribute to synthesis and systemic release of cytokines and chemokines in response to adenovirus sensing. Finally, we review host factors that can limit cytokine and chemokine expression and discuss currently available and potential future interventional approaches that allow for the mitigation of the severity of the cytokine storm syndrome. Effective cytokine-targeted interventional approaches may improve the safety of systemic adenovirus delivery and thus broaden the potential clinical utility of adenovirus-based therapeutic vectors.
Topics: Adenoviridae; Adenoviridae Infections; Chemokines; Cytokine Release Syndrome; Cytokines; Humans; Immunity, Innate
PubMed: 35632630
DOI: 10.3390/v14050888 -
Frontiers in Public Health 2022Human adenovirus (HAdV) is a common virus, but the infections it causes are relatively uncommon. At the same time, the methods for the detection of HAdV are varied,... (Review)
Review
Human adenovirus (HAdV) is a common virus, but the infections it causes are relatively uncommon. At the same time, the methods for the detection of HAdV are varied, among which viral culture is still the gold standard. HAdV infection is usually self-limited but can also cause clinically symptomatic in lots of organs and tissues, of which human adenovirus pneumonia is the most common. In contrast, human adenovirus hepatitis is rarely reported. However, HAdV hepatitis has a high fatality rate once it occurs, especially in immunocompromised patients. Although human adenovirus hepatitis has some pathological and imaging features, its clinical symptoms are not typical. Therefore, HAdV hepatitis is not easy to be found in the clinic. There are kinds of treatments to treat this disease, but few are absolutely effective. In view of the above reasons, HAdV hepatitis is a disease that is difficult to be found in time. We reviewed and summarized the previously reported cases, hoping to bring some relatively common characteristics to clinicians, so as to facilitate early detection, early diagnosis, and early treatment of patients.
Topics: Adenovirus Infections, Human; Adenoviruses, Human; Humans; Immunocompromised Host; Pneumonia
PubMed: 35570934
DOI: 10.3389/fpubh.2022.878161 -
Nature May 2023As of August 2022, clusters of acute severe hepatitis of unknown aetiology in children have been reported from 35 countries, including the USA. Previous studies have...
As of August 2022, clusters of acute severe hepatitis of unknown aetiology in children have been reported from 35 countries, including the USA. Previous studies have found human adenoviruses (HAdVs) in the blood from patients in Europe and the USA, although it is unclear whether this virus is causative. Here we used PCR testing, viral enrichment-based sequencing and agnostic metagenomic sequencing to analyse samples from 16 HAdV-positive cases from 1 October 2021 to 22 May 2022, in parallel with 113 controls. In blood from 14 cases, adeno-associated virus type 2 (AAV2) sequences were detected in 93% (13 of 14), compared to 4 (3.5%) of 113 controls (P < 0.001) and to 0 of 30 patients with hepatitis of defined aetiology (P < 0.001). In controls, HAdV type 41 was detected in blood from 9 (39.1%) of the 23 patients with acute gastroenteritis (without hepatitis), including 8 of 9 patients with positive stool HAdV testing, but co-infection with AAV2 was observed in only 3 (13.0%) of these 23 patients versus 93% of cases (P < 0.001). Co-infections by Epstein-Barr virus, human herpesvirus 6 and/or enterovirus A71 were also detected in 12 (85.7%) of 14 cases, with higher herpesvirus detection in cases versus controls (P < 0.001). Our findings suggest that the severity of the disease is related to co-infections involving AAV2 and one or more helper viruses.
Topics: Child; Humans; Acute Disease; Adenovirus Infections, Human; Coinfection; Dependovirus; Epstein-Barr Virus Infections; Hepatitis; Herpesvirus 4, Human; Herpesvirus 6, Human; Enterovirus A, Human; Helper Viruses
PubMed: 36996871
DOI: 10.1038/s41586-023-05949-1 -
American Journal of Transplantation :... Jul 2022
Topics: Acute Disease; Adenoviridae Infections; Alabama; Child; Hepatitis; Humans
PubMed: 35789534
DOI: 10.1111/ajt.16665 -
Viruses Feb 2021Human adenoviruses cause disease at multiple mucosal sites, including the respiratory, gastrointestinal, and genitourinary tracts, and are common agents of... (Review)
Review
Human adenoviruses cause disease at multiple mucosal sites, including the respiratory, gastrointestinal, and genitourinary tracts, and are common agents of conjunctivitis. One site of infection that has received sparse attention is the cornea, a transparent tissue and the window of the eye. While most adenovirus infections are self-limited, corneal inflammation (keratitis) due to adenovirus can persist or recur for months to years after infection, leading to reduced vision, discomfort, and light sensitivity. Topical corticosteroids effectively suppress late adenovirus keratitis but are associated with vision-threatening side effects. In this short review, we summarize current knowledge on infection of the cornea by adenoviruses, including corneal epithelial cell receptors and determinants of corneal tropism. We briefly discuss mechanisms of stromal keratitis due to adenovirus infection, and review an emerging therapy to mitigate adenovirus corneal infections based on evolving knowledge of corneal epithelial receptor usage.
Topics: Adenoviridae Infections; Adenoviruses, Human; Animals; Cornea; Corneal Diseases; Humans
PubMed: 33668417
DOI: 10.3390/v13020293