Special Issue "Adenovirus Pathogenesis"

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Animal Viruses".

Deadline for manuscript submissions: closed (30 September 2020).

Special Issue Editors

Dr. Annasara Lenman
Website
Guest Editor
Section of Virology, Department of Clinical Microbiology, Umeå University, SE-90185 Umeå, Sweden; Institute for Experimental Virology, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hannover, Germany
Interests: virus–host interactions, gastrointestinal viruses
Prof. Dr. Niklas Arnberg
Website
Guest Editor
Section of Virology, Department of Clinical Microbiology, Umeå University, SE-90185 Umeå, Sweden
Interests: Virus–host cell interactions: implications for tropism, treatment, and targeting

Special Issue Information

Dear Colleagues,

Adenoviruses constitute a common cause of disease in humans, which includes infection in airways, gut, eyes, but also in lymphoid tissue, urinary tract, and liver. Adenovirus infections can be both acute and persistent, and the latter are a common cause of death in immunocompromised patients. There are no approved drugs against this pathogen, implying that studies to better understand its basic biology and pathogenesis are urgently needed. In this Special Issue, we would like to address the molecular and cellular mechanisms of adenovirus infection and pathogenesis. This includes the molecular determinants of cell and tissue tropism, life cycle, transmission in the host, mechanisms of cell death and tissue damage, as well as modulation and evasion of the host’s immune defense. We welcome all paper formats, including short and regular original articles and reviews. For participants of the 14th International Adenovirus Meeting in Spain (https://iam2020.atlantacongress.org/), a 10% discount on Article Processing Charges will be applied.

Dr. Annasara Lenman
Prof. Dr. Niklas Arnberg
Guest Editors

Manuscript Submission Information

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Keywords

  • Human adenovirus
  • Viral pathogenesis
  • Virus–host interactions
  • Immune defense
  • Life cycle
  • Replication
  • Tropism
  • Persistence
  • Antiviral targets

Published Papers (11 papers)

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Research

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Open AccessArticle
House Dust Mite Exposure Causes Increased Susceptibility of Nasal Epithelial Cells to Adenovirus Infection
Viruses 2020, 12(10), 1151; https://doi.org/10.3390/v12101151 - 11 Oct 2020
Abstract
Adenovirus (AdV) infections in the respiratory tract may cause asthma exacerbation and allergic predisposition, and the house dust mite (HDM) may aggravate virus-induced asthma exacerbations. However, the underlying mechanisms of whether and how AdV affects asthmatic patients remains unclear. To address this question, [...] Read more.
Adenovirus (AdV) infections in the respiratory tract may cause asthma exacerbation and allergic predisposition, and the house dust mite (HDM) may aggravate virus-induced asthma exacerbations. However, the underlying mechanisms of whether and how AdV affects asthmatic patients remains unclear. To address this question, we investigated nasal epithelial cells (NAEPCs) derived from a pediatric exacerbation study cohort for experimental analyses. We analyzed twenty-one different green-fluorescent protein- and luciferase-tagged AdV types in submerged 2D and organotypic 3D cell culture models. Transduction experiments revealed robust transduction of AdV type 5 (AdV5) in NAEPCs, which was associated with an increased uptake of AdV5 in the presence of HDM. In healthy and asthmatic NAEPCs exposed to HDM before infection, we observed a time- and dose-dependent increase of AdV5 uptake associated with upregulation of entry receptors for AdV5. Furthermore, electron microscopic and histologic analyses of 3D cell cultures revealed an impairment of the respiratory cilia after HDM exposition. This ex vivo pilot study shows the impact of AdV infection and HDM exposition in a primary cell culture model for asthma. Full article
(This article belongs to the Special Issue Adenovirus Pathogenesis)
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Open AccessArticle
Binding Mechanism Elucidation of the Acute Respiratory Disease Causing Agent Adenovirus of Serotype 7 to Desmoglein-2
Viruses 2020, 12(10), 1075; https://doi.org/10.3390/v12101075 - 25 Sep 2020
Abstract
The study of viruses causing acute respiratory distress syndromes (ARDS) is more essential than ever at a time when a virus can create a global pandemic in a matter of weeks. Among human adenoviruses, adenovirus of serotype 7 (HAdV7) is one of the [...] Read more.
The study of viruses causing acute respiratory distress syndromes (ARDS) is more essential than ever at a time when a virus can create a global pandemic in a matter of weeks. Among human adenoviruses, adenovirus of serotype 7 (HAdV7) is one of the most virulent serotypes. This virus regularly re-emerges in Asia and has just been the cause of several deaths in the United States. A critical step of the virus life cycle is the attachment of the knob domain of the fiber (HAd7K) to the cellular receptor desmoglein-2 (DSG2). Complexes between the fiber knob and two extracellular domains of DSG2 have been produced. Their characterization by biochemical and biophysical methods show that these two domains are sufficient for the interaction and that the trimeric HAd7K could accommodate up to three DSG2 receptor molecules. The cryo-electron microscopy (cryo-EM) structure of these complexes at 3.1 Å resolution confirmed the biochemical data, and allowed the identification of the critical amino acid residues for this interaction, which shows similarities with other DSG2 interacting adenoviruses, despite a low homology in the primary sequences. Full article
(This article belongs to the Special Issue Adenovirus Pathogenesis)
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Open AccessArticle
Differential Effects of Human Adenovirus E1A Protein Isoforms on Aerobic Glycolysis in A549 Human Lung Epithelial Cells
Viruses 2020, 12(6), 610; https://doi.org/10.3390/v12060610 - 03 Jun 2020
Abstract
Viruses alter a multitude of host-cell processes to create a more optimal environment for viral replication. This includes altering metabolism to provide adequate substrates and energy required for replication. Typically, viral infections induce a metabolic phenotype resembling the Warburg effect, with an upregulation [...] Read more.
Viruses alter a multitude of host-cell processes to create a more optimal environment for viral replication. This includes altering metabolism to provide adequate substrates and energy required for replication. Typically, viral infections induce a metabolic phenotype resembling the Warburg effect, with an upregulation of glycolysis and a concurrent decrease in cellular respiration. Human adenovirus (HAdV) has been observed to induce the Warburg effect, which can be partially attributed to the adenovirus protein early region 4, open reading frame 1 (E4orf1). E4orf1 regulates a multitude of host-cell processes to benefit viral replication and can influence cellular metabolism through the transcription factor avian myelocytomatosis viral oncogene homolog (MYC). However, E4orf1 does not explain the full extent of Warburg-like HAdV metabolic reprogramming, especially the accompanying decrease in cellular respiration. The HAdV protein early region 1A (E1A) also modulates the function of the infected cell to promote viral replication. E1A can interact with a wide variety of host-cell proteins, some of which have been shown to interact with metabolic enzymes independently of an interaction with E1A. To determine if the HAdV E1A proteins are responsible for reprogramming cell metabolism, we measured the extracellular acidification rate and oxygen consumption rate of A549 human lung epithelial cells with constitutive endogenous expression of either of the two major E1A isoforms. This was followed by the characterization of transcript levels for genes involved in glycolysis and cellular respiration, and related metabolic pathways. Cells expressing the 13S encoded E1A isoform had drastically increased baseline glycolysis and lower maximal cellular respiration than cells expressing the 12S encoded E1A isoform. Cells expressing the 13S encoded E1A isoform exhibited upregulated expression of glycolysis genes and downregulated expression of cellular respiration genes. However, tricarboxylic acid cycle genes were upregulated, resembling anaplerotic metabolism employed by certain cancers. Upregulation of glycolysis and tricarboxylic acid cycle genes was also apparent in IMR-90 human primary lung fibroblast cells infected with a HAdV-5 mutant virus that expressed the 13S, but not the 12S encoded E1A isoform. In conclusion, it appears that the two major isoforms of E1A differentially influence cellular glycolysis and oxidative phosphorylation and this is at least partially due to the altered regulation of mRNA expression for the genes in these pathways. Full article
(This article belongs to the Special Issue Adenovirus Pathogenesis)
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Open AccessArticle
Adenovirus 14p1 Immunopathogenesis during Lung Infection in the Syrian Hamster
Viruses 2020, 12(6), 595; https://doi.org/10.3390/v12060595 - 30 May 2020
Abstract
Adenovirus (Ad) infections are usually mild and self-limited, with minimal inflammatory responses. During worldwide outbreaks, Ad14p1, an emerging Ad14 variant, has caused severe pulmonary disease, including acute respiratory distress syndrome (ARDS). This increased pathogenicity of Ad14p1 is not completely understood. In initial studies, [...] Read more.
Adenovirus (Ad) infections are usually mild and self-limited, with minimal inflammatory responses. During worldwide outbreaks, Ad14p1, an emerging Ad14 variant, has caused severe pulmonary disease, including acute respiratory distress syndrome (ARDS). This increased pathogenicity of Ad14p1 is not completely understood. In initial studies, we observed that infection of Syrian hamsters with Ad14p1 can cause a patchy bronchopneumonia, with an increased intensity of inflammation, compared to wild type Ad14 infection. The current study compared the dynamics of the immunopathogenesis of Ad14 and Ad14p1 infection of hamster lungs through the first two weeks after infection. Little difference was seen in infection-induced inflammation at day 1. Beginning at day 3, Ad14p1-infected hamsters showed marked inflammation that continued through to day 7. The inflammation began to resolve by day 10 but was still detectable at day 14. In contrast, Ad14-infected hamsters showed little inflammation during the 14-day period of observation. Inflammatory cell type analysis revealed that, at day 1, hamsters infected with either virus had predominantly neutrophil infiltration that began to resolve by day 3. However, at day 5, Ad14p1-infected hamsters had a second wave of neutrophil infiltration that was accompanied by edema which persisted to a variable extent through to day 10. These differences were not explained by an increased Ad14p1 replication rate, compared with Ad14 in vitro, but there was prolonged persistence of Ad14p1 in hamster lungs. There were differences in lung tissue cytokine and chemokine responses to Ad14p1 vs. Ad14 infection that might account for the increased leukocyte infiltrates in Ad14p1-infected hamsters. This animal model characterization provides the basis for future translational studies of the viral genetic mechanisms that control the increased immunopathogenesis of the emergent, Ad14p1 strain. Full article
(This article belongs to the Special Issue Adenovirus Pathogenesis)
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Open AccessArticle
A Novel Role for PX, a Structural Protein of Fowl Adenovirus Serotype 4 (FAdV4), as an Apoptosis-Inducer in Leghorn Male Hepatocellular Cell
Viruses 2020, 12(2), 228; https://doi.org/10.3390/v12020228 - 18 Feb 2020
Abstract
Hydropericardium-Hepatitis Syndrome (HHS) caused by Fowl Adenovirus Serotype 4 (FAdV4) infection is a severe threat to the poultry industry worldwide, especially in China since 2015. Recent studies show that FAdV4 induces liver injury through apoptosis. However, the underlying molecular mechanism is still unclear. [...] Read more.
Hydropericardium-Hepatitis Syndrome (HHS) caused by Fowl Adenovirus Serotype 4 (FAdV4) infection is a severe threat to the poultry industry worldwide, especially in China since 2015. Recent studies show that FAdV4 induces liver injury through apoptosis. However, the underlying molecular mechanism is still unclear. We report here that FAdV4 infection caused apoptosis in Leghorn male hepatocellular (LMH) cells and that PX, a structural protein of FAdV4, acted as a major viral factor inducing apoptosis. Furthermore, the nuclear localization of PX is determined by the R/K regions of PX and required for PX-induced apoptosis. Moreover, alanines 11 and 129 of PX are crucial to PX-induced apoptosis. Inhibition of FAdV4-induced apoptosis by caspase inhibitors retarded viral replication, suggesting that PX serves as a virulence factor for FAdV4 infection, which may further our understandings of the pathogenesis of FAdV4 infection. Full article
(This article belongs to the Special Issue Adenovirus Pathogenesis)
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Review

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Open AccessReview
Adenovirus—Extracellular Protein Interactions and Their Impact on Innate Immune Responses by Human Mononuclear Phagocytes
Viruses 2020, 12(12), 1351; https://doi.org/10.3390/v12121351 - 26 Nov 2020
Abstract
The aim of this review is to highlight how, in a syngeneic system, human mononuclear phagocytes respond to environments containing human adenovirus (HAdV) and soluble extracellular proteins that influence their innate immune response. Soluble extracellular proteins, including immunoglobulins, blood clotting factors, proteins of [...] Read more.
The aim of this review is to highlight how, in a syngeneic system, human mononuclear phagocytes respond to environments containing human adenovirus (HAdV) and soluble extracellular proteins that influence their innate immune response. Soluble extracellular proteins, including immunoglobulins, blood clotting factors, proteins of the complement system, and/or antimicrobial peptides (AMPs) can exert direct effects by binding to a virus capsid that modifies interactions with pattern recognition receptors and downstream signaling. In addition, the presence, generation, or secretion of extracellular proteins can indirectly influence the response to HAdVs via the activation and recruitment of cells at the site of infection. Full article
(This article belongs to the Special Issue Adenovirus Pathogenesis)
Open AccessReview
Role of CCCH-Type Zinc Finger Proteins in Human Adenovirus Infections
Viruses 2020, 12(11), 1322; https://doi.org/10.3390/v12111322 - 18 Nov 2020
Abstract
The zinc finger proteins make up a significant part of the proteome and perform a huge variety of functions in the cell. The CCCH-type zinc finger proteins have gained attention due to their unusual ability to interact with RNA and thereby control different [...] Read more.
The zinc finger proteins make up a significant part of the proteome and perform a huge variety of functions in the cell. The CCCH-type zinc finger proteins have gained attention due to their unusual ability to interact with RNA and thereby control different steps of RNA metabolism. Since virus infections interfere with RNA metabolism, dynamic changes in the CCCH-type zinc finger proteins and virus replication are expected to happen. In the present review, we will discuss how three CCCH-type zinc finger proteins, ZC3H11A, MKRN1, and U2AF1, interfere with human adenovirus replication. We will summarize the functions of these three cellular proteins and focus on their potential pro- or anti-viral activities during a lytic human adenovirus infection. Full article
(This article belongs to the Special Issue Adenovirus Pathogenesis)
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Open AccessReview
Synthesis, Structure, and Function of Human Adenovirus Small Non-Coding RNAs
Viruses 2020, 12(10), 1182; https://doi.org/10.3390/v12101182 - 19 Oct 2020
Cited by 1
Abstract
Human adenoviruses (HAdVs) are common pathogens causing a variety of respiratory, ocular and gastrointestinal diseases. To accomplish their efficient replication, HAdVs take an advantage of viral small non-coding RNAs (sncRNAs), which have multiple roles during the virus lifecycle. Three of the best-characterized HAdV [...] Read more.
Human adenoviruses (HAdVs) are common pathogens causing a variety of respiratory, ocular and gastrointestinal diseases. To accomplish their efficient replication, HAdVs take an advantage of viral small non-coding RNAs (sncRNAs), which have multiple roles during the virus lifecycle. Three of the best-characterized HAdV sncRNAs; VA RNA, mivaRNA and MLP-TSS-sRNA will be discussed in the present review. Even though VA RNA has been extensively characterized during the last 60 years, this multifunctional molecule continues to surprise us as more of its structural secrets unfold. Likely, the recent developments on mivaRNA and MLP-TSS-sRNA synthesis and function highlight the importance of these sncRNA in virus replication. Collectively, we will summarize the old and new knowledge about these three viral sncRNAs with focus on their synthesis, structure and functions. Full article
(This article belongs to the Special Issue Adenovirus Pathogenesis)
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Open AccessReview
En Guard! The Interactions between Adenoviruses and the DNA Damage Response
Viruses 2020, 12(9), 996; https://doi.org/10.3390/v12090996 - 07 Sep 2020
Cited by 1
Abstract
Virus–host cell interactions include several skirmishes between the virus and its host, and the DNA damage response (DDR) network is one of their important battlegrounds. Although some aspects of the DDR are exploited by adenovirus (Ad) to improve virus replication, especially at the [...] Read more.
Virus–host cell interactions include several skirmishes between the virus and its host, and the DNA damage response (DDR) network is one of their important battlegrounds. Although some aspects of the DDR are exploited by adenovirus (Ad) to improve virus replication, especially at the early phase of infection, a large body of evidence demonstrates that Ad devotes many of its proteins, including E1B-55K, E4orf3, E4orf4, E4orf6, and core protein VII, and utilizes varied mechanisms to inhibit the DDR. These findings indicate that the DDR would strongly restrict Ad replication if allowed to function efficiently. Various Ad serotypes inactivate DNA damage sensors, including the Mre11-Rad50-Nbs1 (MRN) complex, DNA-dependent protein kinase (DNA-PK), and Poly (ADP-ribose) polymerase 1 (PARP-1). As a result, these viruses inhibit signaling via DDR transducers, such as the ataxia-telangiectasia mutated (ATM) and ATM- and Rad3-related (ATR) kinases, to downstream effectors. The different Ad serotypes utilize both shared and distinct mechanisms to inhibit various branches of the DDR. The aim of this review is to understand the interactions between Ad proteins and the DDR and to appreciate how these interactions contribute to viral replication. Full article
(This article belongs to the Special Issue Adenovirus Pathogenesis)
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Open AccessReview
The Adenovirus Dodecahedron: Beyond the Platonic Story
Viruses 2020, 12(7), 718; https://doi.org/10.3390/v12070718 - 02 Jul 2020
Abstract
Many geometric forms are found in nature, some of them adhering to mathematical laws or amazing aesthetic rules. One of the best-known examples in microbiology is the icosahedral shape of certain viruses with 20 triangular facets and 12 edges. What is less known, [...] Read more.
Many geometric forms are found in nature, some of them adhering to mathematical laws or amazing aesthetic rules. One of the best-known examples in microbiology is the icosahedral shape of certain viruses with 20 triangular facets and 12 edges. What is less known, however, is that a complementary object displaying 12 faces and 20 edges called a ‘dodecahedron’ can be produced in huge amounts during certain adenovirus replication cycles. The decahedron was first described more than 50 years ago in the human adenovirus (HAdV3) viral cycle. Later on, the expression of this recombinant scaffold, combined with improvements in cryo-electron microscopy, made it possible to decipher the structural determinants underlying their architecture. Recently, this particle, which mimics viral entry, was used to fish the long elusive adenovirus receptor, desmoglein-2, which serves as a cellular docking for some adenovirus serotypes. This breakthrough enabled the understanding of the physiological role played by the dodecahedral particles, showing that icosahedral and dodecahedral particles live more than a simple platonic story. All these points are developed in this review, and the potential use of the dodecahedron in therapeutic development is discussed. Full article
(This article belongs to the Special Issue Adenovirus Pathogenesis)
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Open AccessReview
Intestinal HAdV Infection: Tissue Specificity, Persistence, and Implications for Antiviral Therapy
Viruses 2019, 11(9), 804; https://doi.org/10.3390/v11090804 - 30 Aug 2019
Cited by 6
Abstract
Human adenovirus (HAdV) causes infections predominantly in early childhood and the tissue tropism of specific HAdV species determines the clinical manifestation, including infections of the gastrointestinal tract, respiratory tract, and keratoconjunctivitis. Why HAdV shows such a tropism has not yet been fully elucidated, [...] Read more.
Human adenovirus (HAdV) causes infections predominantly in early childhood and the tissue tropism of specific HAdV species determines the clinical manifestation, including infections of the gastrointestinal tract, respiratory tract, and keratoconjunctivitis. Why HAdV shows such a tropism has not yet been fully elucidated, but in the intestine different mechanisms for virus entry or resistence to immune modulatory factors have been described. Recently identified antiviral strategies by interferons provide evidence about the repression of E1A and maybe even promote HAdV persistence. The presence of HAdV in a persistent status in the gut is of importance in the setting of pediatric stem cell transplant recipients where HAdV detection in stool usually preceds clinical signs and severe infections are related to mortality. The reactivation of persistent intestinal HAdV infections in these patients needs further investigation also with regard to successful therapy options. In addition, several newly identified recombinant HAdV types have been isolated from stool samples, thus raising the question of possible recombination events in the gut. In this review, intestinal HAdV infections are discussed in relation to the tissue tropism, persistence, recombination, and new in-vitro models to enhance the knowledge about virus–host interactions and support the development of new treatment approaches. Full article
(This article belongs to the Special Issue Adenovirus Pathogenesis)
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