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Microorganisms
Special Issues
Novel Approaches for Developing Antiviral and Vaccine Therapies for Enteroviruses
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Novel Approaches for Developing Antiviral and Vaccine Therapies for Enteroviruses

A special issue of Microorganisms (ISSN 2076-2607). This special issue belongs to the section "Antimicrobial Agents and Resistance".

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 19951

Special Issue Editor

Dr. Varpu Marjomaki

E-Mail Website
Guest Editor
Department of Biological and Environmental Science Division of Cell and Molecular Biology/Nanoscience Center, University of Jyväskylä, Jyväskylä, Finland
Interests: endosomes; endocytosis; lysosome; enteroviruses

Special Issue Information

Dear Colleagues,

Enteroviruses are human pathogens which infect a large number of people on a yearly basis, causing acute infections but also contributing to chronic conditions such as asthma, Type I diabetes, and allergies. Enteroviruses being low-fidelity viruses, mutated versions with often more virulent outcomes appear in different parts of the world. Out of approximately 116 enterovirus serotypes, at least 45 new serotypes have emerged within approximately the last ten years. Notorious virulent nonpolio enteroviruses causing difficult outbreaks include EV71, EV68, and EV30, to name but a few. Despite their prevalence and difficult symptoms, there are still few vaccines and antivirals on the market. There is room for new ideas and strategies to combat enterovirus infection. New developments call for in-depth understanding of the key aspects of infection. While potential viral capsid binders have some interesting new additions and a lot of interest is around pocket factor mimics, evolutionarily conserved aspects of viral infection, such as replication and translation ,are attractive targets for potential broadly acting antivirals.

This Special Issue on enteroviruses calls for various aspects on antiviral and vaccine therapies for enteroviruses, including novel ideas, strategies, and previous developments.

Dr. Varpu Marjomaki
Guest Editor

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.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Microorganisms is an international peer-reviewed open access monthly journal published by MDPI.

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.

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Published Papers (5 papers)

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Research

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20 pages, 11718 KiB  
Article
Echovirus-30 Infection Alters Host Proteins in Lipid Rafts at the Cerebrospinal Fluid Barrier In Vitro
by Marie Wiatr, Simon Staubach, Ricardo Figueiredo, Carolin Stump-Guthier, Hiroshi Ishikawa, Christian Schwerk, Horst Schroten, Franz-Georg Hanisch, Henriette Rudolph and Tobias Tenenbaum
Microorganisms 2020, 8(12), 1958; https://doi.org/10.3390/microorganisms8121958 - 10 Dec 2020
Cited by 2 | Viewed by 2083
Abstract
Echovirus-30 (E-30) is a non-polio enterovirus responsible for meningitis outbreaks in children worldwide. To gain access to the central nervous system (CNS), E-30 first has to cross the blood-brain barrier (BBB) or the blood-cerebrospinal fluid barrier (BCSFB). E-30 may use lipid rafts of [...] Read more.
Echovirus-30 (E-30) is a non-polio enterovirus responsible for meningitis outbreaks in children worldwide. To gain access to the central nervous system (CNS), E-30 first has to cross the blood-brain barrier (BBB) or the blood-cerebrospinal fluid barrier (BCSFB). E-30 may use lipid rafts of the host cells to interact with and to invade the BCSFB. To study enteroviral infection of the BCSFB, an established in vitro model based on human immortalized brain choroid plexus papilloma (HIBCPP) cells has been used. Here, we investigated the impact of E-30 infection on the protein content of the lipid rafts at the BCSFB in vitro. Mass spectrometry analysis following E-30 infection versus uninfected conditions revealed differential abundancy in proteins implicated in cellular adhesion, cytoskeleton remodeling, and endocytosis/vesicle budding. Further, we evaluated the blocking of endocytosis via clathrin/dynamin blocking and its consequences for E-30 induced barrier disruption. Interestingly, blocking of endocytosis had no impact on the capacity of E-30 to induce loss of barrier properties in HIBCPP cells. Altogether, these data highlight the impact of E-30 on HIBCPP cells microdomain as an important factor for host cell alteration. Full article
(This article belongs to the Special Issue Novel Approaches for Developing Antiviral and Vaccine Therapies for Enteroviruses)
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23 pages, 4115 KiB  
Article
Detection of Viral −RNA and +RNA Strands in Enterovirus-Infected Cells and Tissues
by Sami Salmikangas, Jutta E. Laiho, Kerttu Kalander, Mira Laajala, Anni Honkimaa, Iryna Shanina, Sami Oikarinen, Marc S. Horwitz, Heikki Hyöty and Varpu Marjomäki
Microorganisms 2020, 8(12), 1928; https://doi.org/10.3390/microorganisms8121928 - 4 Dec 2020
Cited by 4 | Viewed by 3410
Abstract
The current methods to study the distribution and dynamics of viral RNA molecules inside infected cells are not ideal, as electron microscopy and immunohistochemistry can only detect mature virions, and quantitative real-time PCR does not reveal localized distribution of RNAs. We demonstrated here [...] Read more.
The current methods to study the distribution and dynamics of viral RNA molecules inside infected cells are not ideal, as electron microscopy and immunohistochemistry can only detect mature virions, and quantitative real-time PCR does not reveal localized distribution of RNAs. We demonstrated here the branched DNA in situ hybridization (bDNA ISH) technology to study both the amount and location of the emerging −RNA and +RNA during acute and persistent enterovirus infections. According to our results, the replication of the viral RNA started 2–3 h after infection and the translation shortly after at 3–4 h post-infection. The replication hotspots with newly emerging −RNA were located quite centrally in the cell, while the +RNA production and most likely virion assembly took place in the periphery of the cell. We also discovered that the pace of replication of −RNA and +RNA strands was almost identical, and −RNA was absent during antiviral treatments. ViewRNA ISH with our custom probes also showed a good signal during acute and persistent enterovirus infections in cell and mouse models. Considering these results, along with the established bDNA FISH protocol modified by us, the effects of antiviral drugs and the emergence of enterovirus RNAs in general can be studied more effectively. Full article
(This article belongs to the Special Issue Novel Approaches for Developing Antiviral and Vaccine Therapies for Enteroviruses)
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21 pages, 8364 KiB  
Article
Genetic Adaptation of Coxsackievirus B1 during Persistent Infection in Pancreatic Cells
by Anni Honkimaa, Bryn Kimura, Amir-Babak Sioofy-Khojine, Jake Lin, Jutta Laiho, Sami Oikarinen and Heikki Hyöty
Microorganisms 2020, 8(11), 1790; https://doi.org/10.3390/microorganisms8111790 - 15 Nov 2020
Cited by 11 | Viewed by 3313
Abstract
Coxsackie B (CVB) viruses have been associated with type 1 diabetes. We have recently observed that CVB1 was linked to the initiation of the autoimmune process leading to type 1 diabetes in Finnish children. Viral persistency in the pancreas is currently considered as [...] Read more.
Coxsackie B (CVB) viruses have been associated with type 1 diabetes. We have recently observed that CVB1 was linked to the initiation of the autoimmune process leading to type 1 diabetes in Finnish children. Viral persistency in the pancreas is currently considered as one possible mechanism. In the current study persistent infection was established in pancreatic ductal and beta cell lines (PANC-1 and 1.1B4) using four different CVB1 strains, including the prototype strain and three clinical isolates. We sequenced 5′ untranslated region (UTR) and regions coding for structural and non-structural proteins and the second single open reading frame (ORF) protein of all persisting CVB1 strains using next generation sequencing to identify mutations that are common for all of these strains. One mutation, K257R in VP1, was found from all persisting CVB1 strains. The mutations were mainly accumulated in viral structural proteins, especially at BC, DE, EF loops and C-terminus of viral capsid protein 1 (VP1), the puff region of VP2, the knob region of VP3 and infection-enhancing epitope of VP4. This showed that the capsid region of the viruses sustains various changes during persistency some of which could be hallmark(s) of persistency. Full article
(This article belongs to the Special Issue Novel Approaches for Developing Antiviral and Vaccine Therapies for Enteroviruses)
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13 pages, 1559 KiB  
Article
Structural Insight into CVB3-VLP Non-Adjuvanted Vaccine
by Minna M. Hankaniemi, Mo A. Baikoghli, Virginia M. Stone, Li Xing, Outi Väätäinen, Saana Soppela, Amirbabak Sioofy-Khojine, Niila V. V. Saarinen, Tingwei Ou, Brandon Anson, Heikki Hyöty, Varpu Marjomäki, Malin Flodström-Tullberg, R. Holland Cheng, Vesa P. Hytönen and Olli H. Laitinen
Microorganisms 2020, 8(9), 1287; https://doi.org/10.3390/microorganisms8091287 - 24 Aug 2020
Cited by 9 | Viewed by 5273
Abstract
Coxsackievirus B (CVB) enteroviruses are common pathogens that can cause acute and chronic myocarditis, dilated cardiomyopathy, aseptic meningitis, and they are hypothesized to be a causal factor in type 1 diabetes. The licensed enterovirus vaccines and those currently in clinical development are traditional [...] Read more.
Coxsackievirus B (CVB) enteroviruses are common pathogens that can cause acute and chronic myocarditis, dilated cardiomyopathy, aseptic meningitis, and they are hypothesized to be a causal factor in type 1 diabetes. The licensed enterovirus vaccines and those currently in clinical development are traditional inactivated or live attenuated vaccines. Even though these vaccines work well in the prevention of enterovirus diseases, new vaccine technologies, like virus-like particles (VLPs), can offer important advantages in the manufacturing and epitope engineering. We have previously produced VLPs for CVB3 and CVB1 in insect cells. Here, we describe the production of CVB3-VLPs with enhanced production yield and purity using an improved purification method consisting of tangential flow filtration and ion exchange chromatography, which is compatible with industrial scale production. We also resolved the CVB3-VLP structure by Cryo-Electron Microscopy imaging and single particle reconstruction. The VLP diameter is 30.9 nm on average, and it is similar to Coxsackievirus A VLPs and the expanded enterovirus cell-entry intermediate (the 135s particle), which is ~2 nm larger than the mature virion. High neutralizing and total IgG antibody levels, the latter being a predominantly Th2 type (IgG1) phenotype, were detected in C57BL/6J mice immunized with non-adjuvanted CVB3-VLP vaccine. The structural and immunogenic data presented here indicate the potential of this improved methodology to produce highly immunogenic enterovirus VLP-vaccines in the future. Full article
(This article belongs to the Special Issue Novel Approaches for Developing Antiviral and Vaccine Therapies for Enteroviruses)
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Review

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23 pages, 9880 KiB  
Review
Epidemiology and Sequence-Based Evolutionary Analysis of Circulating Non-Polio Enteroviruses
by David M. Brown, Yun Zhang and Richard H. Scheuermann
Microorganisms 2020, 8(12), 1856; https://doi.org/10.3390/microorganisms8121856 - 25 Nov 2020
Cited by 21 | Viewed by 5289
Abstract
Enteroviruses (EVs) are positive-sense RNA viruses, with over 50,000 nucleotide sequences publicly available. While most human infections are typically associated with mild respiratory symptoms, several different EV types have also been associated with severe human disease, especially acute flaccid paralysis (AFP), particularly with [...] Read more.
Enteroviruses (EVs) are positive-sense RNA viruses, with over 50,000 nucleotide sequences publicly available. While most human infections are typically associated with mild respiratory symptoms, several different EV types have also been associated with severe human disease, especially acute flaccid paralysis (AFP), particularly with endemic members of the EV-B species and two pandemic types—EV-A71 and EV-D68—that appear to be responsible for recent widespread outbreaks. Here we review the recent literature on the prevalence, characteristics, and circulation dynamics of different enterovirus types and combine this with an analysis of the sequence coverage of different EV types in public databases (e.g., the Virus Pathogen Resource). This evaluation reveals temporal and geographic differences in EV circulation and sequence distribution, highlighting recent EV outbreaks and revealing gaps in sequence coverage. Phylogenetic analysis of the EV genus shows the relatedness of different EV types. Recombination analysis of the EV-A species provides evidence for recombination as a mechanism of genomic diversification. The absence of broadly protective vaccines and effective antivirals makes human enteroviruses important pathogens of public health concern. Full article
(This article belongs to the Special Issue Novel Approaches for Developing Antiviral and Vaccine Therapies for Enteroviruses)
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