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Adenovirus Cell and Immune Interactions

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A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Viral Immunology, Vaccines, and Antivirals".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 32879

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Prof. Dr. Glen R. Nemerow

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Scripps Research Institute, Department of Microbiology and Immunology, San Diego, USA
Interests: virus-host receptor interactions; adenovirus structural biology; adenovirus-innate immune interactions
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Ever since their discovery in the early 1950s, human adenoviruses (HAdVs), the cause of respiratory diseases of young children, have been the subject of intense basic research as well as efforts to engineer HAdV vectors to ameliorate human diseases. Although much information has been gleaned over the past 67 years from laboratory and clinical investigations, we still have an incomplete picture of the critical associations of HAdV with host cells and specific components of the immune system. An ability to uncover additional information will likely influence the future success (or failure) for exploiting HAdV vectors for gene and vaccine therapies.

Each chapter in this series will highlight the efforts and progress made to acquire basic knowledge of adenovirus host interactions and will indicate particular areas that remain to be uncovered. Topics in this new series include key steps in HAdV–host cell interactions as well as structure-based investigations of virus and virus capsid protein associations with cell receptors and innate immune molecules. These topics will culminate with discussions on examples of HAdV vector design and how these approaches are influenced by the accumulation of knowledge of host–vector interactions.

Prof. Glen R. Nemerow
Guest Editor

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Keywords

adenovirus
gene therapy
vaccine
immune system
respiratory disease

Related Special Issue

Adenovirus Cell and Immune Interactions 2.0 in Viruses (2 articles)

Published Papers (11 papers)

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Research

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15 pages, 3495 KiB

Open AccessArticle

Refined Capsid Structure of Human Adenovirus D26 at 3.4 Å Resolution

by Vijay S. Reddy, Xiaodi Yu and Michael A. Barry

Viruses 2022, 14(2), 414; https://doi.org/10.3390/v14020414 - 17 Feb 2022

Cited by 2 | Viewed by 1987

Abstract

Various adenoviruses are being used as viral vectors for the generation of vaccines against chronic and emerging diseases (e.g., AIDS, COVID-19). Here, we report the improved capsid structure for one of these vectors, human adenovirus D26 (HAdV-D26), at 3.4 Å resolution, by reprocessing the previous cryo-electron microscopy dataset and obtaining a refined model. In addition to overall improvements in the model, the highlights of the structure include (1) locating a segment of the processed peptide of VIII that was previously believed to be released from the mature virions, (2) reorientation of the helical appendage domain (APD) of IIIa situated underneath the vertex region relative to its counterpart observed in the cleavage defective (ts1) mutant of HAdV-C5 that resulted in the loss of interactions between the APD and hexon bases, and (3) the revised conformation of the cleaved N-terminal segments of pre-protein VI (pVIn), located in the hexon cavities, is highly conserved, with notable stacking interactions between the conserved His13 and Phe18 residues. Taken together, the improved model of HAdV-D26 capsid provides a better understanding of protein–protein interactions in HAdV capsids and facilitates the efforts to modify and/or design adenoviral vectors with altered properties. Last but not least, we provide some insights into clotting factors (e.g., FX and PF4) binding to AdV vectors. Full article

(This article belongs to the Special Issue Adenovirus Cell and Immune Interactions)

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12 pages, 2169 KiB

Open AccessArticle

IgG-Complexed Adenoviruses Induce Human Plasmacytoid Dendritic Cell Activation and Apoptosis

by Thi Thu Phuong Tran, Tuan Hiep Tran and Eric J. Kremer

Viruses 2021, 13(9), 1699; https://doi.org/10.3390/v13091699 - 27 Aug 2021

Cited by 4 | Viewed by 1817

Abstract

Following repeat exposure to many human adenoviruses (HAdVs), most adults harbour long-lived B- and T-cell responses. Combined, this response typically protects us for years from re-infection by the same HAdV type. In spite of these immune responses, some HAdV types are associated with persistent infections that constitute a life-threatening risk when an individual’s T-cell response is compromised. By contrast, patients with B-cell deficiencies do not appear to be at a greater risk of HAdV disease. This dichotomy begs the question of the secondary role of anti-HAdV antibodies during host defence. In this study, we explored IgG-complexed (IC)-HAdV5 and primary human plasmacytoid dendritic cell (pDC) interactions. We found that IC-HAdV5 are efficiently internalized in pDCs, stimulate their activation through TLR9 signalling, and cause apoptosis. These data may help reconcile the enigma of robust immune response to HAdVs, while concurrently allowing persistence. Full article

(This article belongs to the Special Issue Adenovirus Cell and Immune Interactions)

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14 pages, 3025 KiB

Open AccessArticle

In Vitro and In Vivo Evaluation of Human Adenovirus Type 49 as a Vector for Therapeutic Applications

by Emily A. Bates, John R. Counsell, Sophie Alizert, Alexander T. Baker, Natalie Suff, Ashley Boyle, Angela C. Bradshaw, Simon N. Waddington, Stuart A. Nicklin, Andrew H. Baker and Alan L. Parker

Viruses 2021, 13(8), 1483; https://doi.org/10.3390/v13081483 - 28 Jul 2021

Cited by 5 | Viewed by 3446

Abstract

The human adenovirus phylogenetic tree is split across seven species (A–G). Species D adenoviruses offer potential advantages for gene therapy applications, with low rates of pre-existing immunity detected across screened populations. However, many aspects of the basic virology of species D—such as their cellular tropism, receptor usage, and in vivo biodistribution profile—remain unknown. Here, we have characterized human adenovirus type 49 (HAdV-D49)—a relatively understudied species D member. We report that HAdV-D49 does not appear to use a single pathway to gain cell entry, but appears able to interact with various surface molecules for entry. As such, HAdV-D49 can transduce a broad range of cell types in vitro, with variable engagement of blood coagulation FX. Interestingly, when comparing in vivo biodistribution to adenovirus type 5, HAdV-D49 vectors show reduced liver targeting, whilst maintaining transduction of lung and spleen. Overall, this presents HAdV-D49 as a robust viral vector platform for ex vivo manipulation of human cells, and for in vivo applications where the therapeutic goal is to target the lung or gain access to immune cells in the spleen, whilst avoiding liver interactions, such as intravascular vaccine applications. Full article

(This article belongs to the Special Issue Adenovirus Cell and Immune Interactions)

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11 pages, 2149 KiB

Open AccessCommunication

Intracellular Sequestration of the NKG2D Ligand MIC B by Species F Adenovirus

by Edson R. A. Oliveira, Lenong Li and Marlene Bouvier

Viruses 2021, 13(7), 1289; https://doi.org/10.3390/v13071289 - 01 Jul 2021

Cited by 3 | Viewed by 2223

Abstract

The enteric human adenoviruses of species F (HAdVs-F), which comprise HAdV-F40 and HAdV-F41, are significant pathogens that cause acute gastroenteritis in children worldwide. The early transcription unit 3 (E3) of HAdVs-F is markedly different from that of all other HAdV species. To date, the E3 proteins unique to HAdVs-F have not been characterized and the mechanism by which HAdVs-F evade immune defenses in the gastrointestinal (GI) tract is poorly understood. Here, we show that HAdV-F41 infection of human intestinal HCT116 cells upregulated the expression of MHC class I-related chain A (MIC A) and MIC B relative to uninfected cells. Our results also showed that, for MIC B, this response did not however result in a significant increase of MIC B on the cell surface. Instead, MIC B was largely sequestered intracellularly. Thus, although HAdV-F41 infection of HCT116 cells upregulated MIC B expression, the ligand remained inside infected cells. A similar observation could not be made for MIC A in these cells. Our preliminary findings represent a novel function of HAdVs-F that may enable these viruses to evade immune surveillance by natural killer (NK) cells in the infected gut, thereby paving the way for the future investigation of their unique E3 proteins. Full article

(This article belongs to the Special Issue Adenovirus Cell and Immune Interactions)

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11 pages, 1844 KiB

Open AccessCommunication

Differential Regulation of Cellular FAM111B by Human Adenovirus C Type 5 E1 Oncogenes

by Wing-Hang Ip, Britta Wilkens, Anastasia Solomatina, Judith Martin, Michael Melling, Paloma Hidalgo, Luca D. Bertzbach, Thomas Speiseder and Thomas Dobner

Viruses 2021, 13(6), 1015; https://doi.org/10.3390/v13061015 - 28 May 2021

Cited by 4 | Viewed by 2967

Abstract

The adenovirus type 5 (HAdV-C5) E1 transcription unit encodes regulatory proteins that are essential for viral replication and transformation. Among these, E1A and E1B-55K act as key multifunctional HAdV-C5 proteins involved in various steps of the viral replication cycle and in virus-induced cell transformation. In this context, HAdV-C5-mediated dysregulations of cellular factors such as the tumor suppressors p53 and pRB have been intensively investigated. However, cellular components of downstream events that could affect infection and viral transformation are widely unknown. We recently observed that cellular FAM111B is highly regulated in an E1A-dependent fashion. Intriguingly, previous reports suggest that FAM111B might play roles in tumorigenesis, but its exact functions are not known to date. Here, we set out to investigate the role of FAM111B in HAdV-C5 infections. We found that (i) FAM111B levels are upregulated early and downregulated late during infection, that (ii) FAM111B expression is differentially regulated, that (iii) FAM111B expression levels depend on the presence of E1B-55K and E4orf6 and that (iv) a FAM111B knockdown increases HAdV-C5 replication. Our data indicate that FAM111B acts as an anti-adenoviral host factor that is involved in host cell defense mechanisms in productive HAdV-C5 infection. Moreover, these findings suggest that FAM111B might play an important role in the host antiviral immune response that is counteracted by HAdV-C5 E1B-55K and E4orf6 oncoproteins. Full article

(This article belongs to the Special Issue Adenovirus Cell and Immune Interactions)

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18 pages, 2848 KiB

Open AccessArticle

Heparan Sulfate Is a Cellular Receptor for Enteric Human Adenoviruses

by Anandi Rajan, Elin Palm, Fredrik Trulsson, Sarah Mundigl, Miriam Becker, B. David Persson, Lars Frängsmyr and Annasara Lenman

Viruses 2021, 13(2), 298; https://doi.org/10.3390/v13020298 - 14 Feb 2021

Cited by 7 | Viewed by 2532

Abstract

Human adenovirus (HAdV)-F40 and -F41 are leading causes of diarrhea and diarrhea-associated mortality in children under the age of five, but the mechanisms by which they infect host cells are poorly understood. HAdVs initiate infection through interactions between the knob domain of the fiber capsid protein and host cell receptors. Unlike most other HAdVs, HAdV-F40 and -F41 possess two different fiber proteins—a long fiber and a short fiber. Whereas the long fiber binds to the Coxsackievirus and adenovirus receptor (CAR), no binding partners have been identified for the short fiber. In this study, we identified heparan sulfate (HS) as an interaction partner for the short fiber of enteric HAdVs. We demonstrate that exposure to acidic pH, which mimics the environment of the stomach, inactivates the interaction of enteric adenovirus with CAR. However, the short fiber:HS interaction is resistant to and even enhanced by acidic pH, which allows attachment to host cells. Our results suggest a switch in receptor usage of enteric HAdVs after exposure to acidic pH and add to the understanding of the function of the short fibers. These results may also be useful for antiviral drug development and the utilization of enteric HAdVs for clinical applications such as vaccine development. Full article

(This article belongs to the Special Issue Adenovirus Cell and Immune Interactions)

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19 pages, 3674 KiB

Open AccessArticle

Structure-Based Modeling of Complement C4 Mediated Neutralization of Adenovirus

by Corey C. Emerson and Phoebe L. Stewart

Viruses 2021, 13(1), 111; https://doi.org/10.3390/v13010111 - 15 Jan 2021

Cited by 2 | Viewed by 2154

Abstract

Adenovirus (AdV) infection elicits a strong immune response with the production of neutralizing antibodies and opsonization by complement and coagulation factors. One anti-hexon neutralizing antibody, called 9C12, is known to activate the complement cascade, resulting in the deposition of complement component C4b on the capsid, and the neutralization of the virus. The mechanism of AdV neutralization by C4b is independent of downstream complement proteins and involves the blockage of the release of protein VI, which is required for viral escape from the endosome. To investigate the structural basis underlying how C4b blocks the uncoating of AdV, we built a model for the complex of human adenovirus type-5 (HAdV5) with 9C12, together with complement components C1 and C4b. This model positions C4b near the Arg-Gly-Asp (RGD) loops of the penton base. There are multiple amino acids in the RGD loop that might serve as covalent binding sites for the reactive thioester of C4b. Molecular dynamics simulations with a multimeric penton base and C4b indicated that stabilizing interactions may form between C4b and multiple RGD loops. We propose that C4b deposition on one RGD loop leads to the entanglement of C4b with additional RGD loops on the same penton base multimer and that this entanglement blocks AdV uncoating. Full article

(This article belongs to the Special Issue Adenovirus Cell and Immune Interactions)

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Review

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12 pages, 1974 KiB

Open AccessReview

Human Adenovirus Species D Interactions with Corneal Stromal Cells

by Jaya Rajaiya, Amrita Saha, Xiaohong Zhou and James Chodosh

Viruses 2021, 13(12), 2505; https://doi.org/10.3390/v13122505 - 14 Dec 2021

Cited by 4 | Viewed by 2683

Abstract

Notable among the many communicable agents known to infect the human cornea is the human adenovirus, with less than ten adenoviruses having corneal tropism out of more than 100 known types. The syndrome of epidemic keratoconjunctivitis (EKC), caused principally by human adenovirus, presents acutely with epithelial keratitis, and later with stromal keratitis that can be chronic and recurrent. In this review, we discuss the current state of knowledge regarding the molecular biology of adenovirus infection of corneal stromal cells, among which the fibroblast-like keratocyte is the most predominant, in order to elucidate basic pathophysiologic mechanisms of stromal keratitis in the human patient with EKC. Full article

(This article belongs to the Special Issue Adenovirus Cell and Immune Interactions)

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24 pages, 8575 KiB

Open AccessReview

Genetic and Chemical Capsid Modifications of Adenovirus Vectors to Modulate Vector–Host Interactions

by Denice Weklak, Daniel Pembaur, Georgia Koukou, Franziska Jönsson, Claudia Hagedorn and Florian Kreppel

Viruses 2021, 13(7), 1300; https://doi.org/10.3390/v13071300 - 02 Jul 2021

Cited by 9 | Viewed by 4710

Abstract

Adenovirus-based vectors are playing an important role as efficacious genetic vaccines to fight the current COVID-19 pandemic. Furthermore, they have an enormous potential as oncolytic vectors for virotherapy and as vectors for classic gene therapy. However, numerous vector–host interactions on a cellular and noncellular level, including specific components of the immune system, must be modulated in order to generate safe and efficacious vectors for virotherapy or classic gene therapy. Importantly, the current widespread use of Ad vectors as vaccines against COVID-19 will induce antivector immunity in many humans. This requires the development of strategies and techniques to enable Ad-based vectors to evade pre-existing immunity. In this review article, we discuss the current status of genetic and chemical capsid modifications as means to modulate the vector–host interactions of Ad-based vectors. Full article

(This article belongs to the Special Issue Adenovirus Cell and Immune Interactions)

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31 pages, 1978 KiB

Open AccessReview

Understanding Post Entry Sorting of Adenovirus Capsids; A Chance to Change Vaccine Vector Properties

by Coralie F. Daussy, Noémie Pied and Harald Wodrich

Viruses 2021, 13(7), 1221; https://doi.org/10.3390/v13071221 - 24 Jun 2021

Cited by 10 | Viewed by 3485

Abstract

Adenovirus vector-based genetic vaccines have emerged as a powerful strategy against the SARS-CoV-2 health crisis. This success is not unexpected because adenoviruses combine many desirable features of a genetic vaccine. They are highly immunogenic and have a low and well characterized pathogenic profile paired with technological approachability. Ongoing efforts to improve adenovirus-vaccine vectors include the use of rare serotypes and non-human adenoviruses. In this review, we focus on the viral capsid and how the choice of genotypes influences the uptake and subsequent subcellular sorting. We describe how understanding capsid properties, such as stability during the entry process, can change the fate of the entering particles and how this translates into differences in immunity outcomes. We discuss in detail how mutating the membrane lytic capsid protein VI affects species C viruses’ post-entry sorting and briefly discuss if such approaches could have a wider implication in vaccine and/or vector development. Full article

(This article belongs to the Special Issue Adenovirus Cell and Immune Interactions)

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6 pages, 520 KiB

Open AccessCase Report

DIC-Like Syndrome Following Administration of ChAdOx1 nCov-19 Vaccination

by Gerardo Casucci and Domenico Acanfora

Viruses 2021, 13(6), 1046; https://doi.org/10.3390/v13061046 - 01 Jun 2021

Cited by 7 | Viewed by 2940

Abstract

In recent weeks, adverse reactions have been reported after administration of Oxford–AstraZeneca chimpanzee adenovirus vectored vaccine ChAdOx1 nCoV-19 (AZD1222), in particular thrombus formation, which has led several European Countries to discontinue administration of this vaccine. On March 8, 2021, the European Medicines Agency Safety Committee did not confirm this probable association. We report the case of a patient who developed disseminated intravascular coagulation after the first dose of Oxford-Astra Zeneca vaccine, which resolved in a few days with the administration of dexamethasone and enoxaparin. This work demonstrates the safety of the Oxford-Astra Zeneca vaccine and that any development of side effects can be easily managed with a prompt diagnosis and in a short time with a few commonly used drugs. Full article

(This article belongs to the Special Issue Adenovirus Cell and Immune Interactions)

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