Editorial

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Open AccessEditorial

Special Issue “Cell, Organoid and Animal Models to Study Pathogenic Human RNA Viruses”

by Akio Adachi and Masako Nomaguchi

Viruses 2021, 13(10), 1943; https://0-doi-org.brum.beds.ac.uk/10.3390/v13101943 - 28 Sep 2021

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Abstract

Numerous species of RNA viruses pathogenic for humans are present worldwide [...] Full article

(This article belongs to the Special Issue Cell, Organoid and Animal Models to Study Pathogenic Human RNA Viruses)

Research

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11 pages, 2394 KiB

Open AccessArticle

Neutralizing Antibody Induction Associated with a Germline Immunoglobulin Gene Polymorphism in Neutralization-Resistant SIVsmE543-3 Infection

by Yuto Nomura, Saori Matsuoka, Midori Okazaki, Takeo Kuwata, Tetsuro Matano and Hiroshi Ishii

Viruses 2021, 13(6), 1181; https://0-doi-org.brum.beds.ac.uk/10.3390/v13061181 - 21 Jun 2021

Cited by 1 | Viewed by 1850

Abstract

Antibody responses are crucial for the control of virus infection. Understanding of the mechanism of antibody induction is important for the development of a vaccine eliciting effective anti-virus antibodies. Virus-specific B cell receptor (BCR)/antibody repertoires are different among individuals, but determinants for this [...] Read more.

Antibody responses are crucial for the control of virus infection. Understanding of the mechanism of antibody induction is important for the development of a vaccine eliciting effective anti-virus antibodies. Virus-specific B cell receptor (BCR)/antibody repertoires are different among individuals, but determinants for this difference remain largely unclear. We have recently reported that a germline BCR immunoglobulin (IgG) gene polymorphism (VH3.33_ET or VH3.33_VI) in rhesus macaques is the determinant for induction of potent B404-class anti-simian immunodeficiency virus (SIV) neutralizing antibodies in neutralization-sensitive SIVsmH635FC infection. In the present study, we examined whether neutralization-resistant SIVsmE543-3 infection can induce the anti-SIV neutralizing antibodies associated with the germline VH3.33 polymorphism. Anti-SIVsmE543-3 neutralizing antibodies were induced in all the macaques possessing the VH3.33_ET allele, but not in those without VH3.33_ET, in the chronic phase of SIVsmE543-3 infection. Next generation sequencing analysis of BCR VH genes found B404-class antibody sequences only in those with VH3.33_ET. These results indicate that anti-SIVsmE543-3 neutralizing antibody induction associated with the germline BCR IgG gene polymorphism can be triggered by infection with neutralization-resistant SIVsmE543-3. This animal model would be useful for the elucidation of the mechanism of potent antibody induction against neutralization-resistant viruses. Full article

(This article belongs to the Special Issue Cell, Organoid and Animal Models to Study Pathogenic Human RNA Viruses)

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11 pages, 2246 KiB

Open AccessCommunication

Mutated Measles Virus Matrix and Fusion Protein Influence Viral Titer In Vitro and Neuro-Invasion in Lewis Rat Brain Slice Cultures

by Johannes Busch, Soroth Chey, Michael Sieg, Thomas W. Vahlenkamp and Uwe G. Liebert

Viruses 2021, 13(4), 605; https://0-doi-org.brum.beds.ac.uk/10.3390/v13040605 - 01 Apr 2021

Cited by 5 | Viewed by 2129

Abstract

Measles virus (MV) can cause severe acute diseases as well as long-lasting clinical deteriorations due to viral-induced immunosuppression and neuronal manifestation. How the virus enters the brain and manages to persist in neuronal tissue is not fully understood. Various mutations in the viral [...] Read more.

Measles virus (MV) can cause severe acute diseases as well as long-lasting clinical deteriorations due to viral-induced immunosuppression and neuronal manifestation. How the virus enters the brain and manages to persist in neuronal tissue is not fully understood. Various mutations in the viral genes were found in MV strains isolated from patient brains. In this study, reverse genetics was used to introduce mutations in the fusion, matrix and polymerase genes of MV. The generated virus clones were characterized in cell culture and used to infect rat brain slice cultures. A mutation in the carboxy-terminal domain of the matrix protein (R293Q) promoted the production of progeny virions. This effect was observed in Vero cells irrespective of the expression of the signaling lymphocyte activation molecule (SLAM). Furthermore, a mutation in the fusion protein (I225M) induced syncytia formation on Vero cells in the absence of SLAM and promoted viral spread throughout the rat brain slices. In this study, a solid ex vivo model was established to elucidate the MV mutations contributing to neural manifestation. Full article

(This article belongs to the Special Issue Cell, Organoid and Animal Models to Study Pathogenic Human RNA Viruses)

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17 pages, 3752 KiB

Open AccessArticle

Broadly Active Antiviral Compounds Disturb Zika Virus Progeny Release Rescuing Virus-Induced Toxicity in Brain Organoids

by Aleksandra Pettke, Marianna Tampere, Robin Pronk, Olov Wallner, Anna Falk, Ulrika Warpman Berglund, Thomas Helleday, Ali Mirazimi and Marjo-Riitta Puumalainen

Viruses 2021, 13(1), 37; https://0-doi-org.brum.beds.ac.uk/10.3390/v13010037 - 29 Dec 2020

Cited by 14 | Viewed by 4140

Abstract

RNA viruses have gained plenty of attention during recent outbreaks of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Zika virus (ZIKV), and Ebola virus. ZIKV is a vector borne Flavivirus that is spread by mosquitoes and it mainly infects neuronal progenitor cells. One [...] Read more.

RNA viruses have gained plenty of attention during recent outbreaks of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Zika virus (ZIKV), and Ebola virus. ZIKV is a vector borne Flavivirus that is spread by mosquitoes and it mainly infects neuronal progenitor cells. One hallmark of congenital ZIKV disease is a reduced brain size in fetuses, leading to severe neurological defects. The World Health Organization (WHO) is urging the development of new antiviral treatments against ZIKV, as there are no efficient countermeasures against ZIKV disease. Previously, we presented a new class of host-targeting antivirals active against a number of pathogenic RNA viruses, such as SARS-CoV-2. Here, we show the transfer of the image-based phenotypic antiviral assay to ZIKV-infected brain cells, followed by mechanism-of-action studies and a proof-of-concept study in a three-dimensional (3D) organoid model. The novel antiviral compounds showed a therapeutic window against ZIKV in several cell models and rescued ZIKV-induced neurotoxicity in brain organoids. The compound’s mechanism-of-action was pinpointed to late steps in the virus life cycle, impairing the formation of new virus particles. Collectively, in this study, we expand the antiviral activity of new small molecule inhibitors to a new virus class of Flaviviruses, but also uncover compounds’ mechanism of action, which are important for the further development of antivirals. Full article

(This article belongs to the Special Issue Cell, Organoid and Animal Models to Study Pathogenic Human RNA Viruses)

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Review

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11 pages, 4515 KiB

Open AccessReview

Nonhuman Primate Models of Zika Virus Infection and Disease during Pregnancy

by Nicole N. Haese, Victoria H. J. Roberts, Athena Chen, Daniel N. Streblow, Terry K. Morgan and Alec J. Hirsch

Viruses 2021, 13(10), 2088; https://0-doi-org.brum.beds.ac.uk/10.3390/v13102088 - 16 Oct 2021

Cited by 12 | Viewed by 2882

Abstract

Since the explosive outbreak of Zika virus in Brazil and South/Central America in 2015–2016, the frequency of infections has subsided, but Zika virus remains present in this region as well as other tropical and sub-tropical areas of the globe. The most alarming aspect [...] Read more.

Since the explosive outbreak of Zika virus in Brazil and South/Central America in 2015–2016, the frequency of infections has subsided, but Zika virus remains present in this region as well as other tropical and sub-tropical areas of the globe. The most alarming aspect of Zika virus infection is its association with severe birth defects when infection occurs in pregnant women. Understanding the mechanism of Zika virus pathogenesis, which comprises features unique to Zika virus as well as shared with other teratogenic pathogens, is key to future prophylactic or therapeutic interventions. Nonhuman primate-based research has played a significant role in advancing our knowledge of Zika virus pathogenesis, especially with regard to fetal infection. This review summarizes what we have learned from these models and potential future research directions. Full article

(This article belongs to the Special Issue Cell, Organoid and Animal Models to Study Pathogenic Human RNA Viruses)

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13 pages, 1918 KiB

Open AccessReview

Human Rotavirus Reverse Genetics Systems to Study Viral Replication and Pathogenesis

by Satoshi Komoto, Saori Fukuda, Takayuki Murata and Koki Taniguchi

Viruses 2021, 13(9), 1791; https://0-doi-org.brum.beds.ac.uk/10.3390/v13091791 - 08 Sep 2021

Cited by 4 | Viewed by 2744

Abstract

Human rotaviruses (HuRVAs) are highly important causes of acute gastroenteritis in infants and young children worldwide. A lack of reliable and reproducible reverse genetics systems for HuRVAs has limited a proper understanding of HuRVA biology and also the rational design of live-attenuated vaccines. [...] Read more.

Human rotaviruses (HuRVAs) are highly important causes of acute gastroenteritis in infants and young children worldwide. A lack of reliable and reproducible reverse genetics systems for HuRVAs has limited a proper understanding of HuRVA biology and also the rational design of live-attenuated vaccines. Since the development of the first reverse genetics system for RVAs (partially plasmid-based reverse genetics system) in 2006, there have been many efforts with the goal of generating infectious recombinant HuRVAs entirely from cloned cDNAs. However, the establishment of a HuRVA reverse genetics system was very challenging until 2019. This review article provides an overview of the historical background of the recent development of long-awaited HuRVA reverse genetics systems, beginning with the generation of recombinant human-simian reassortant RVAs with the aid of a helper virus in 2006 and the generation of recombinant animal (simian) RVAs in a helper virus-free manner in 2017, and culminating in the generation of recombinant HuRVAs entirely from plasmid cDNAs in 2019. Notably, the original HuRVA reverse genetics system has already been optimized to increase the efficiency of virus generation. Although the application of HuRVA reverse genetics systems has only just been initiated, these technologies will help to answer HuRVA research questions regarding viral replication and pathogenicity that could not be addressed before, and to develop next-generation vaccines and intestine-specific rotaviral vectors. Full article

(This article belongs to the Special Issue Cell, Organoid and Animal Models to Study Pathogenic Human RNA Viruses)

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18 pages, 285 KiB

Open AccessReview

Animal Models for Influenza Research: Strengths and Weaknesses

by Thi-Quyen Nguyen, Rare Rollon and Young-Ki Choi

Viruses 2021, 13(6), 1011; https://0-doi-org.brum.beds.ac.uk/10.3390/v13061011 - 28 May 2021

Cited by 29 | Viewed by 4493

Abstract

Influenza remains one of the most significant public health threats due to its ability to cause high morbidity and mortality worldwide. Although understanding of influenza viruses has greatly increased in recent years, shortcomings remain. Additionally, the continuous mutation of influenza viruses through genetic [...] Read more.

Influenza remains one of the most significant public health threats due to its ability to cause high morbidity and mortality worldwide. Although understanding of influenza viruses has greatly increased in recent years, shortcomings remain. Additionally, the continuous mutation of influenza viruses through genetic reassortment and selection of variants that escape host immune responses can render current influenza vaccines ineffective at controlling seasonal epidemics and potential pandemics. Thus, there is a knowledge gap in the understanding of influenza viruses and a corresponding need to develop novel universal vaccines and therapeutic treatments. Investigation of viral pathogenesis, transmission mechanisms, and efficacy of influenza vaccine candidates requires animal models that can recapitulate the disease. Furthermore, the choice of animal model for each research question is crucial in order for researchers to acquire a better knowledge of influenza viruses. Herein, we reviewed the advantages and limitations of each animal model—including mice, ferrets, guinea pigs, swine, felines, canines, and non-human primates—for elucidating influenza viral pathogenesis and transmission and for evaluating therapeutic agents and vaccine efficacy. Full article

(This article belongs to the Special Issue Cell, Organoid and Animal Models to Study Pathogenic Human RNA Viruses)

21 pages, 1018 KiB

Open AccessReview

Experimental Methods to Study the Pathogenesis of Human Enteric RNA Viruses

by Somya Aggarwal, Ebrahim Hassan and Megan T. Baldridge

Viruses 2021, 13(6), 975; https://0-doi-org.brum.beds.ac.uk/10.3390/v13060975 - 25 May 2021

Cited by 5 | Viewed by 4097

Abstract

Every year, millions of children are infected with viruses that target the gastrointestinal tract, causing acute gastroenteritis and diarrheal illness. Indeed, approximately 700 million episodes of diarrhea occur in children under five annually, with RNA viruses norovirus, rotavirus, and astrovirus serving as major [...] Read more.

Every year, millions of children are infected with viruses that target the gastrointestinal tract, causing acute gastroenteritis and diarrheal illness. Indeed, approximately 700 million episodes of diarrhea occur in children under five annually, with RNA viruses norovirus, rotavirus, and astrovirus serving as major causative pathogens. Numerous methodological advancements in recent years, including the establishment of novel cultivation systems using enteroids as well as the development of murine and other animal models of infection, have helped provide insight into many features of viral pathogenesis. However, many aspects of enteric viral infections remain elusive, demanding further study. Here, we describe the different in vitro and in vivo tools available to explore different pathophysiological attributes of human enteric RNA viruses, highlighting their advantages and limitations depending upon the question being explored. In addition, we discuss key areas and opportunities that would benefit from further methodological progress. Full article

(This article belongs to the Special Issue Cell, Organoid and Animal Models to Study Pathogenic Human RNA Viruses)

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17 pages, 1635 KiB

Open AccessReview

In Vitro Lung Models and Their Application to Study SARS-CoV-2 Pathogenesis and Disease

by Natalie Heinen, Mara Klöhn, Eike Steinmann and Stephanie Pfaender

Viruses 2021, 13(5), 792; https://0-doi-org.brum.beds.ac.uk/10.3390/v13050792 - 28 Apr 2021

Cited by 23 | Viewed by 9341

Abstract

SARS-CoV-2 has spread across the globe with an astonishing velocity and lethality that has put scientist and pharmaceutical companies worldwide on the spot to develop novel treatment options and reliable vaccination for billions of people. To combat its associated disease COVID-19 and potentially [...] Read more.

SARS-CoV-2 has spread across the globe with an astonishing velocity and lethality that has put scientist and pharmaceutical companies worldwide on the spot to develop novel treatment options and reliable vaccination for billions of people. To combat its associated disease COVID-19 and potentially newly emerging coronaviruses, numerous pre-clinical cell culture techniques have progressively been used, which allow the study of SARS-CoV-2 pathogenesis, basic replication mechanisms, and drug efficiency in the most authentic context. Hence, this review was designed to summarize and discuss currently used in vitro and ex vivo cell culture systems and will illustrate how these systems will help us to face the challenges imposed by the current SARS-CoV-2 pandemic. Full article

(This article belongs to the Special Issue Cell, Organoid and Animal Models to Study Pathogenic Human RNA Viruses)

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23 pages, 394 KiB

Open AccessReview

Perspectives on Non-BLT Humanized Mouse Models for Studying HIV Pathogenesis and Therapy

by Kazutaka Terahara, Ryutaro Iwabuchi and Yasuko Tsunetsugu-Yokota

Viruses 2021, 13(5), 776; https://0-doi-org.brum.beds.ac.uk/10.3390/v13050776 - 28 Apr 2021

Cited by 7 | Viewed by 3279

Abstract

A variety of humanized mice, which are reconstituted only with human hematopoietic stem cells (HSC) or with fetal thymus and HSCs, have been developed and widely utilized as in vivo animal models of HIV-1 infection. The models represent some aspects of HIV-mediated pathogenesis [...] Read more.

A variety of humanized mice, which are reconstituted only with human hematopoietic stem cells (HSC) or with fetal thymus and HSCs, have been developed and widely utilized as in vivo animal models of HIV-1 infection. The models represent some aspects of HIV-mediated pathogenesis in humans and are useful for the evaluation of therapeutic regimens. However, there are several limitations in these models, including their incomplete immune responses and poor distribution of human cells to the secondary lymphoid tissues. These limitations are common in many humanized mouse models and are critical issues that need to be addressed. As distinct defects exist in each model, we need to be cautious about the experimental design and interpretation of the outcomes obtained using humanized mice. Considering this point, we mainly characterize the current conventional humanized mouse reconstituted only with HSCs and describe past achievements in this area, as well as the potential contributions of the humanized mouse models for the study of HIV pathogenesis and therapy. We also discuss the use of various technologies to solve the current problems. Humanized mice will contribute not only to the pre-clinical evaluation of anti-HIV regimens, but also to a deeper understanding of basic aspects of HIV biology. Full article

(This article belongs to the Special Issue Cell, Organoid and Animal Models to Study Pathogenic Human RNA Viruses)

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