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Special Issue "The Multifaceted Parvoviridae Family: From Pathogens to Therapeutics"

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A special issue of Pathogens (ISSN 2076-0817). This special issue belongs to the section "Vaccines and Therapeutic Developments".

Deadline for manuscript submissions: 1 December 2023 | Viewed by 14695

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Dr. Assia Angelova

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Clinical Cooperation Unit Virotherapy, German Cancer Research Center, Im Neuenheimer Feld 242, 69120 Heidelberg, Germany
Interests: parvoviruses; oncolytic viruses; cancer; cancer virotherapy; cancer viroimmunotherapy

Prof. Dr. Jean Rommelaere

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Dear Colleagues,

Parvoviridae is a family of small (23–28 nm), non-enveloped viruses with an icosahedral capsid, which encloses a linear single-stranded 4-6 kb DNA genome flanked on both ends by short terminal hairpins. The family includes three subfamilies, twenty-three genera, and more than a hundred virus species. Notably, some of these viruses are animal or human pathogens, while others are used for gene therapy and oncolytic virus therapy purposes. This Special Issue of Pathogens aims at bringing together original research and review articles to provide the readers with a comprehensive picture of the multifaceted role of Parvoviridae in both disease induction and treatment. Recent discoveries, current state of the art, challenges, and prospects are discussed, with a particular focus on parvovirus newly identified associations with disease and exciting applications to the therapy of genetic disorders, including cancer.

Dr. Assia Angelova
Prof. Dr. Jean Rommelaere
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

parvoviridae
gene therapy
oncolytic virus therapy
pathogenicity
genetic disorders

Published Papers (5 papers)

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Research

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Open AccessArticle

Oncolytic Rodent Protoparvoviruses Evade a TLR- and RLR-Independent Antiviral Response in Transformed Cells

and

Pathogens 2023, 12(4), 607; https://doi.org/10.3390/pathogens12040607 - 17 Apr 2023

Viewed by 880

Abstract

The oncolytic rodent protoparvoviruses (PVs) minute virus of mice (MVMp) and H-1 parvovirus (H-1PV) are promising cancer viro-immunotherapy candidates capable of both exhibiting direct oncolytic activities and inducing anticancer immune responses (AIRs). Type-I interferon (IFN) production is instrumental for the activation of an efficient AIR. The present study aims at characterizing the molecular mechanisms underlying PV modulation of IFN induction in host cells. MVMp and H-1PV triggered IFN production in semi-permissive normal mouse embryonic fibroblasts (MEFs) and human peripheral blood mononuclear cells (PBMCs), but not in permissive transformed/tumor cells. IFN production triggered by MVMp in primary MEFs required PV replication and was independent of the pattern recognition receptors (PRRs) Toll-like (TLR) and RIG-like (RLR) receptors. PV infection of (semi-)permissive cells, whether transformed or not, led to nuclear translocation of the transcription factors NFĸB and IRF3, hallmarks of PRR signaling activation. Further evidence showed that PV replication in (semi-)permissive cells resulted in nuclear accumulation of dsRNAs capable of activating mitochondrial antiviral signaling (MAVS)-dependent cytosolic RLR signaling upon transfection into naïve cells. This PRR signaling was aborted in PV-infected neoplastic cells, in which no IFN production was detected. Furthermore, MEF immortalization was sufficient to strongly reduce PV-induced IFN production. Pre-infection of transformed/tumor but not of normal cells with MVMp or H-1PV prevented IFN production by classical RLR ligands. Altogether, our data indicate that natural rodent PVs regulate the antiviral innate immune machinery in infected host cells through a complex mechanism. In particular, while rodent PV replication in (semi-)permissive cells engages a TLR-/RLR-independent PRR pathway, in transformed/tumor cells this process is arrested prior to IFN production. This virus-triggered evasion mechanism involves a viral factor(s), which exert(s) an inhibitory action on IFN production, particularly in transformed/tumor cells. These findings pave the way for the development of second-generation PVs that are defective in this evasion mechanism and therefore endowed with increased immunostimulatory potential through their ability to induce IFN production in infected tumor cells. Full article

(This article belongs to the Special Issue The Multifaceted Parvoviridae Family: From Pathogens to Therapeutics)

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Open AccessArticle

Primate Erythroparvovirus 1 Infection in Patients with Hematological Disorders

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Pathogens 2022, 11(5), 497; https://doi.org/10.3390/pathogens11050497 - 21 Apr 2022

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Abstract

Primate erythroparvovirus 1, commonly referred to as Parvovirus B19 (B19V), is a DNA virus that normally results in a mild childhood infection called “erythema infectiosum”. Besides respiratory spread, B19V can also be transmitted through transfusions, which may result in persistent anemia in immunodeficient hosts. Dialysis patients often face acute or chronic anemia after infection with B19V. Here, we describe the laboratory investigation of 21 patients with hematological disorders for B19V infections. B19V DNA was detected in 13 (62%) of them, with specific IgM antibodies in three of the DNA positives. All 13 patients received treatment and were laboratory-monitored over a period of one year. In only two patients (a 14-year-old child with a kidney transplantation and a 39-year-old patient with aplastic anemia), markers of recent B19V infection were still detectable in follow-up samples. For four B19V DNA positive samples, short sequences could be obtained, which clustered with genotype 1a reference strains. Our findings suggest that all cases of hematological disorders should be examined for specific B19V antibodies and DNA for accurate diagnosis and appropriate patient management. Full article

(This article belongs to the Special Issue The Multifaceted Parvoviridae Family: From Pathogens to Therapeutics)

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Open AccessArticle

Generation and Validation of Monoclonal Antibodies Suitable for Detecting and Monitoring Parvovirus Infections

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Pathogens 2022, 11(2), 208; https://doi.org/10.3390/pathogens11020208 - 04 Feb 2022

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Abstract

For many applications it is necessary to detect target proteins in living cells. This is particularly the case when monitoring viral infections, in which the presence (or absence) of distinct target polypeptides potentially provides vital information about the pathology caused by the agent. To obtain suitable tools with which to monitor parvoviral infections, we thus generated monoclonal antibodies (mAbs) in order to detect the major non-structural protein NS1 in the intracellular environment and tested them for sensitivity and specificity, as well as for cross-reactivity towards related species. Using different immunogens and screening approaches based on indirect immunofluorescence, we describe here a panel of mAbs suitable for monitoring active infections with various parvovirus species by targeting the major non-structural protein NS1. In addition to mAbs detecting the NS1 of parvovirus H-1 (H-1PV) (belonging to the Rodent protoparvovirus 1 species, which is currently under validation as an anti-cancer agent), we generated tools with which to monitor infections by human cutavirus (CuV) and B19 virus (B19V) (belonging to the Primate protoparvovirus 3 and the Primate erythroparvovirus 1 species, respectively, which were both found to persistently infect human tissues). As well as mAbs able to detect NS1 from a broad range of parvoviruses, we obtained entities specific for either (distinct) members of the Rodent protoparvovirus 1 species, human CuV, or human B19V. Full article

(This article belongs to the Special Issue The Multifaceted Parvoviridae Family: From Pathogens to Therapeutics)

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Review

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Open AccessReview

Therapeutic Potential of Engineered Virus-like Particles of Parvovirus B19

Ignacio Sánchez-Moguel

Carmina Montiel

and

Ismael Bustos-Jaimes

Pathogens 2023, 12(8), 1007; https://doi.org/10.3390/pathogens12081007 - 02 Aug 2023

Viewed by 486

Abstract

Virus-like particles (VLPs) comprise one or many structural components of virions, except their genetic material. Thus, VLPs keep their structural properties of cellular recognition while being non-infectious. VLPs of Parvovirus B19 (B19V) can be produced by the heterologous expression of their structural proteins VP1 and VP2 in bacteria. These proteins are purified under denaturing conditions, refolded, and assembled into VLPs. Moreover, chimeric forms of VP2 have been constructed to harbor peptides or functional proteins on the surface of the particles without dropping their competence to form VLPs, serving as presenting nanoparticles. The in-vitro assembly approach offers exciting possibilities for the composition of VLPs, as more than one chimeric form of VP2 can be included in the assembly stage, producing multifunctional VLPs. Here, the heterologous expression and in-vitro assembly of B19V structural proteins and their chimeras are reviewed. Considerations for the engineering of the structural proteins of B19V are also discussed. Finally, the construction of multifunctional VLPs and their future potential as innovative medical tools are examined. Full article

(This article belongs to the Special Issue The Multifaceted Parvoviridae Family: From Pathogens to Therapeutics)

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Open AccessReview

Fantastic AAV Gene Therapy Vectors and How to Find Them—Random Diversification, Rational Design and Machine Learning

Jonas Becker

Julia Fakhiri

and

Dirk Grimm

Pathogens 2022, 11(7), 756; https://doi.org/10.3390/pathogens11070756 - 03 Jul 2022

Cited by 14 | Viewed by 9223

Abstract

Parvoviruses are a diverse family of small, non-enveloped DNA viruses that infect a wide variety of species, tissues and cell types. For over half a century, their intriguing biology and pathophysiology has fueled intensive research aimed at dissecting the underlying viral and cellular mechanisms. Concurrently, their broad host specificity (tropism) has motivated efforts to develop parvoviruses as gene delivery vectors for human cancer or gene therapy applications. While the sum of preclinical and clinical data consistently demonstrates the great potential of these vectors, these findings also illustrate the importance of enhancing and restricting in vivo transgene expression in desired cell types. To this end, major progress has been made especially with vectors based on Adeno-associated virus (AAV), whose capsid is highly amenable to bioengineering, repurposing and expansion of its natural tropism. Here, we provide an overview of the state-of-the-art approaches to create new AAV variants with higher specificity and efficiency of gene transfer in on-target cells. We first review traditional and novel directed evolution approaches, including high-throughput screening of AAV capsid libraries. Next, we discuss programmable receptor-mediated targeting with a focus on two recent technologies that utilize high-affinity binders. Finally, we highlight one of the latest stratagems for rational AAV vector characterization and optimization, namely, machine learning, which promises to facilitate and accelerate the identification of next-generation, safe and precise gene delivery vehicles. Full article

(This article belongs to the Special Issue The Multifaceted Parvoviridae Family: From Pathogens to Therapeutics)

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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Methylation State in the Tumor Cells Determines Sensitivity of the Pancreatic Tumor Cells to the Oncolytic Parvovirus H-1PV
Authors: Matthias Neulinger-Muñoz; Dominik Schaack; Andrea S. Bauer; Thomas Giese; Gabriel A. Salg; Elisa Espinet; Barbara Leuchs; Jürg P.F Nüesch; Miriam Schenk; Michael Volkmar; Nathalia A. Giese
Affiliation: 1 Department of Surgery, European Pancreas Center, University Hospital Heidelberg, Heidelberg, Germany 2 Department of Anesthesiology, University Hospital Heidelberg, Heidelberg, Germany 3 Division of Functional Genomics, German Cancer Research Center (DKFZ), Heidelberg, Germany 4 Institute of Immunology and German Center for Infection Research (DZIF), partner site Heidelberg, University Hospital Heidelberg, Heidelberg, Germany 5 Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany 6 Division of Tumor Virology, German Cancer Research center (DKFZ), Heidelberg, Germany 7 Division of Virus-Associated Carcinogenesis F170, German Cancer Research Center (DKFZ), Heidelberg, Germany 8 Division of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center (DKFZ) and TCR Discovery Platform, Helmholtz-Institute for Translational Oncology by DKFZ (HI-TRON, Mainz, Germany)
Abstract: Pancreatic tumor cells differ in their susceptibility to the oncolytic parvovirus H-1PV. Predicting its oncolytic pawer and sensitizing tumor cells to H-1PV might help to improve its therapeutic applicability. To elucidate potential mechanism of resistance, we performed genome-wide RNAseq profiling in H-1PV-infected PDAC cell lines. Bioinformatic analyses linked oncolytic power to the E2F-pathway and positioned DNTM1, a HERV-inhibitory E2F target, as the most important regulator. Basal DNTM1 levels inversely correlated with IC50-dose in nine tested PDAC cell lines. H-1PV elevated DNMT1 expression to a lesser degree in resistant than in sensitive cells. At the same time, the inhibition of DNMTs with 5-azacytidine (5-AZA) promoted the expression of interferon-stimulated genes (ISGs) in six out of eight tested PDACs and the expression of HERV in only two of them; significant co-elevation occurred only once, in Colo357 cells, a solitary non- mutant p53 variant of PDACs. Whether up- or downregulated by 5-AZA, these ISG levels were reduced by H-1PV. This reduction was proportional to the “basal” loss, thus relating DNMT1 to the regulation of the homeostatic antiviral circuit. Whether DNMT1 is indeed a major target to be reactivated by H-1PV and suppress ISG by reducing HERV abundance or if there is an alternative mechanism of a common regulatory interference remains to be determined.

Title: Parvovirus B19 Infection in Children with Anemia and Kidney Transplantation
Authors: Stefka Krumova; Ivona Andonova; Radostina Stefanova; Polina Miteva; Judith M. Hübschen
Affiliation: 1 National Center of Infectious and Parasitic Diseases, Department Virology, National Reference Laboratory of Measles, Mumps and Rubella, Sofia, Bulgaria; 2 Specialized Hospital for Active Treatment of Children's Diseases „Prof. Dr. Ivan Mitev“EAD, Sofia, Bulgaria; 3 Clinical and Applied Virology group, Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg
Abstract: Parvovirus B19 (B19V) is a single-stranded DNA virus that commonly causes a benign childhood infection typically manifesting as "erythema infectiosum" rash. B19V is a transfusion-transmissible virus and in immunodeficient hosts, this infection can cause persistent anemia. Patients who require dialysis may have increased susceptibility to acute and chronic anemia after parvoviral infection. This study focuses on laboratory testing of transplant recipients with unexplained anemia. A total of 21 children with anemia were screened for B19V infection. We describe B19V infection after kidney transplantation in two (11- and 14-year-old) children. Laboratory tests of follow-up samples from these patients revealed elevated B19V IgM titers and presence of viral DNA. B19V genotype 1a was detected. Patients are not routinely screened for B19V infection. Therefore, the incidence of this infection in renal transplant patients is most likely underestimated and hematological disorders are falsely ascribed to immunosuppressive drugs.

Title: Generation and Validation of Monoclonal Antibodies Suitable to Detect and Monitor Parvovirus Infections
Authors: Claudia Tessmer; Claudia Plotzky; Jana Fees; Hendrik Welsh; Rebecca Eudenbach; Martin Faber; Alicia Simon; Assia L. Angelova; Jean Rommelaere; Ilse Hofmann; Jürg, P.F. Nüesch
Affiliation: 1 Genomics and Proteomics Core Facility, Unit Antibodies, German Cancer Research Center (DKFZ), Heidelberg, Germany; 2 Program Infection, Inflammation and Cancer, Division Virus-Associated Carcinogenesis (F170), German Cancer Research Center (DKFZ), Heidelberg, Germany; 3 Program Infection, Inflammation and Cancer, Clinical Cooperation Unit Virotherapy (F230), German Cancer Research Center (DKFZ), Heidelberg, Germany;
Abstract: For many applications it is mandatory to detect target proteins in living cells. This is in particular the case monitoring viral infections for which the presence (or absence) of distinct target polypeptides potentially provide vital information about the pathology caused by the agent. To obtain suitable tools to monitor parvoviral infections, we thus generated monoclonal antibodies in order to detect the major non-structural protein NS1 in the cellular environment and tested them for sensitivity and specificity as well as cross-reactivity towards related species. Using different immunogens and screening approaches based on indirect immunofluorescence, we describe here a panel of mAbs suitable to monitor active infection of parvovirus species by targeting the major non-structural protein NS1. In addition to mAbs detecting rodent H1-NS1, which is currently under validation as an anti-cancer agent, we generated tools to monitor infections of the human Protoparvovirus “Cutavirus” und the Erythrovirus B19, which both were found persistently infecting human tissues. Besides mAbs detecting NS1 from a broad range of PVs, we obtained entities, discriminating (distinct) rodent PV species from human Protoparvoviruses, B19 and vice versa.

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