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Viruses
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Animal Models for Viral Diseases
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Animal Models for Viral Diseases

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

Deadline for manuscript submissions: closed (31 October 2018) | Viewed by 103512

Special Issue Editors

Prof. John Doorbar

E-Mail Website
Guest Editor
Department of Pathology, University of Cambridge, Cambridge, UK
Interests: papillomavirus; virus tropsim; cervical cancer; tumour viruses; cervical screening
Prof. Ian Goodfellow

E-Mail Website
Guest Editor
Division of Virology, Department of Pathology, University of Cambridge, Addenbrooke's Hospital, Cambrige, UK

Special Issue Information

Dear Colleagues,

While observational studies on clinical materials are essential if we are to properly understand virus-associated disease pathogenesis, it is clear that clinical analysis must be combined with experimental approaches, if we are to fully understand the mechanistic aspects of disease progression. In this scheme, the use of animal disease models lies between experiments that aim to reconstruct of aspects of disease and tissue architecture using in vitro tissue culture methodologies, and as far as it is possible, the clinical evaluation of disease in infected human patients. Historically, the utility of animal models has been restricted by the host and tissue specificity of the virus under investigation, and/or whether an appropriate animal virus, able to cause similar disease in an appropriate laboratory animal can be found. It has often been the case, that virus disease-associations seen in humans, do not extend unmodified to their animal virus counterparts. To use these models requires a clear appreciation of the limitations of the chosen approach. More recently, the use of humanised mice has allowed the direct analysis of human viruses in human cells in the context of a whole animal, and has also been used to understand interaction with a humanised immune system. The increasing sophistication of such models is providing new insight into disease mechanisms, and the development of therapeutic approaches to control infection.

Prof. John Doorbar
Prof. Ian Goodfellow
Guest Editors

Manuscript Submission Information

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Keywords

  • disease models
  • virus infection
  • drug discovery
  • immune therapy
  • disease mechanisms

Published Papers (20 papers)

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Research

Jump to: Review

25 pages, 2674 KiB  
Article
Immunogenicity and Efficacy of a Novel Multi-Antigenic Peptide Vaccine Based on Cross-Reactivity between Feline and Human Immunodeficiency Viruses
by Bikash Sahay, Alek M. Aranyos, Meerambika Mishra, Andrew C. McAvoy, Marcus M. Martin, Riuyu Pu, Sayaka Shiomitsu, Keijiro Shiomitsu, Michael J. Dark, Missa P. Sanou, Shannon R. Roff, Mobeen H. Rathore and Janet K. Yamamoto
Viruses 2019, 11(2), 136; https://doi.org/10.3390/v11020136 - 03 Feb 2019
Cited by 5 | Viewed by 4078
Abstract
For the development of an effective HIV-1 vaccine, evolutionarily conserved epitopes between feline and human immunodeficiency viruses (FIV and HIV-1) were determined by analyzing overlapping peptides from retroviral genomes that induced both anti-FIV/HIV T cell-immunity in the peripheral blood mononuclear cells from the [...] Read more.
For the development of an effective HIV-1 vaccine, evolutionarily conserved epitopes between feline and human immunodeficiency viruses (FIV and HIV-1) were determined by analyzing overlapping peptides from retroviral genomes that induced both anti-FIV/HIV T cell-immunity in the peripheral blood mononuclear cells from the FIV-vaccinated cats and the HIV-infected humans. The conserved T-cell epitopes on p24 and reverse transcriptase were selected based on their robust FIV/HIV-specific CD8+ cytotoxic T lymphocyte (CTL), CD4+ CTL, and polyfunctional T-cell activities. Four such evolutionarily conserved epitopes were formulated into four multiple antigen peptides (MAPs), mixed with an adjuvant, to be tested as FIV vaccine in cats. The immunogenicity and protective efficacy were evaluated against a pathogenic FIV. More MAP/peptide-specific CD4+ than CD8+ T-cell responses were initially observed. By post-third vaccination, half of the MAP/peptide-specific CD8+ T-cell responses were higher or equivalent to those of CD4+ T-cell responses. Upon challenge, 15/19 (78.9%) vaccinated cats were protected, whereas 6/16 (37.5%) control cats remained uninfected, resulting in a protection rate of 66.3% preventable fraction (p = 0.0180). Thus, the selection method used to identify the protective FIV peptides should be useful in identifying protective HIV-1 peptides needed for a highly protective HIV-1 vaccine in humans. Full article
(This article belongs to the Special Issue Animal Models for Viral Diseases)
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11 pages, 1010 KiB  
Article
Different Outcomes of Experimental Hepatitis E Virus Infection in Diverse Mouse Strains, Wistar Rats, and Rabbits
by Josephine Schlosser, Lisa Dähnert, Paul Dremsek, Kerstin Tauscher, Christine Fast, Ute Ziegler, Albrecht Gröner, Rainer G Ulrich, Martin H Groschup and Martin Eiden
Viruses 2019, 11(1), 1; https://doi.org/10.3390/v11010001 - 20 Dec 2018
Cited by 24 | Viewed by 5222
Abstract
Hepatitis E virus (HEV) is the causative agent of acute hepatitis E in humans in developing countries, but autochthonous cases of zoonotic genotype 3 (HEV-3) infection also occur in industrialized countries. In contrast to swine, rats, and rabbits, natural HEV infections in mice [...] Read more.
Hepatitis E virus (HEV) is the causative agent of acute hepatitis E in humans in developing countries, but autochthonous cases of zoonotic genotype 3 (HEV-3) infection also occur in industrialized countries. In contrast to swine, rats, and rabbits, natural HEV infections in mice have not yet been demonstrated. The pig represents a well-established large animal model for HEV-3 infection, but a suitable small animal model mimicking natural HEV-3 infection is currently missing. Therefore, we experimentally inoculated C57BL/6 mice (wild-type, IFNAR−/−, CD4−/−, CD8−/−) and BALB/c nude (nu/nu) mice, Wistar rats, and European rabbits with a wild boar-derived HEV-3 strain and monitored virus replication and shedding, as well as humoral immune responses. HEV RNA and anti-HEV antibodies were detected in one and two out of eight of the rats and all rabbits inoculated, respectively, but not in any of the mouse strains tested. Remarkably, immunosuppressive dexamethasone treatment of rats did not enhance their susceptibility to HEV infection. In rabbits, immunization with recombinant HEV-3 and ratHEV capsid proteins induced protection against HEV-3 challenge. In conclusion, the rabbit model for HEV-3 infection may serve as a suitable alternative to the non-human primate and swine models, and as an appropriate basis for vaccine evaluation studies. Full article
(This article belongs to the Special Issue Animal Models for Viral Diseases)
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18 pages, 2569 KiB  
Article
RVFV Infection in Goats by Different Routes of Inoculation
by Andrea L. Kroeker, Valerie Smid, Carissa Embury-Hyatt, Estella Moffat, Brad Collignon, Oliver Lung, Robbin Lindsay and Hana Weingartl
Viruses 2018, 10(12), 709; https://doi.org/10.3390/v10120709 - 12 Dec 2018
Cited by 7 | Viewed by 3866
Abstract
Rift Valley fever virus (RVFV) is a zoonotic arbovirus of the Phenuiviridae family. Infection causes abortions in pregnant animals, high mortality in neonate animals, and mild to severe symptoms in both people and animals. There is currently an ongoing effort to produce safe [...] Read more.
Rift Valley fever virus (RVFV) is a zoonotic arbovirus of the Phenuiviridae family. Infection causes abortions in pregnant animals, high mortality in neonate animals, and mild to severe symptoms in both people and animals. There is currently an ongoing effort to produce safe and efficacious veterinary vaccines against RVFV in livestock to protect against both primary infection in animals and zoonotic infections in people. To test the efficacy of these vaccines, it is essential to have a reliable challenge model in relevant target species, including ruminants. We evaluated two goat breeds (Nubian and LaMancha), three routes of inoculation (intranasal, mosquito-primed subcutaneous, and subcutaneous) using an infectious dose of 107 pfu/mL, a virus strain from the 2006–2007 Kenyan/Sudan outbreak and compared the effect of using virus stocks produced in either mammalian or mosquito cells. Our results demonstrated that the highest and longest viremia titers were achieved in Nubian goats. The Nubian breed was also efficient at producing clinical signs, consistent viremia (peak viremia: 1.2 × 103–1.0 × 105 pfu/mL serum), nasal and oral shedding of viral RNA (1.5 × 101–8 × 106 genome copies/swab), a systemic infection of tissues, and robust antibody responses regardless of the inoculation route. The Nubian goat breed and a needle-free intranasal inoculation technique could both be utilized in future vaccine and challenge studies. These studies are important for preventing the spread and outbreak of zoonotic viruses like RVFV and are supported by the Canadian-led BSL4ZNet network. Full article
(This article belongs to the Special Issue Animal Models for Viral Diseases)
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15 pages, 1088 KiB  
Article
Pathobiological and Genomic Characterization of a Cold-Adapted Infectious Bronchitis Virus (BP-caKII)
by Seung-Min Hong, Se-Hee An, Chung-Young Lee, Chang-Seon Song, Kang-Seuk Choi, Jae-Hong Kim and Hyuk-Joon Kwon
Viruses 2018, 10(11), 652; https://doi.org/10.3390/v10110652 - 19 Nov 2018
Cited by 4 | Viewed by 3377
Abstract
We established a cold-adapted infectious bronchitis virus (BP-caKII) by passaging a field virus through specific pathogen-free embryonated eggs 20 times at 32 °C. We characterized its growth kinetics and pathogenicity in embryonated eggs, and its tropism and persistence in different tissues from chickens; [...] Read more.
We established a cold-adapted infectious bronchitis virus (BP-caKII) by passaging a field virus through specific pathogen-free embryonated eggs 20 times at 32 °C. We characterized its growth kinetics and pathogenicity in embryonated eggs, and its tropism and persistence in different tissues from chickens; then, we evaluated pathogenicity by using a new premature reproductive tract pathogenicity model. Furthermore, we determined the complete genomic sequence of BP-caKII to understand the genetic changes related to cold adaptation. According to our results, BP-caKII clustered with the KII genotype viruses K2 and KM91, and showed less pathogenicity than K2, a live attenuated vaccine strain. BP-caKII showed delayed viremia, resulting in its delayed dissemination to the kidneys and cecal tonsils compared to K2 and KM91, the latter of which is a pathogenic field strain. A comparative genomics study revealed similar nucleotide sequences between BP-caKII, K2 and KM91 but clearly showed different mutations among them. BP-caKII shared several mutations with K2 (nsp13, 14, 15 and 16) following embryo adaptation but acquired multiple additional mutations in nonstructural proteins (nsp3, 4 and 12), spike proteins and nucleocapsid proteins following cold adaptation. Thus, the establishment of BP-caKII and the identified mutations in this study may provide insight into the genetic background of embryo and cold adaptations, and the attenuation of coronaviruses. Full article
(This article belongs to the Special Issue Animal Models for Viral Diseases)
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12 pages, 1023 KiB  
Article
Pathogenesis of Rift Valley Fever Virus Aerosol Infection in STAT2 Knockout Hamsters
by Brady T. Hickerson, Jonna B. Westover, Arnaud J. Van Wettere, Johanna D. Rigas, Jinxin Miao, Bettina L. Conrad, Neil E. Motter, Zhongde Wang and Brian B. Gowen
Viruses 2018, 10(11), 651; https://doi.org/10.3390/v10110651 - 19 Nov 2018
Cited by 5 | Viewed by 3962
Abstract
Rift Valley fever virus (RVFV) is an emerging pathogen capable of causing severe disease in livestock and humans and can be transmitted by multiple routes including aerosol exposure. Several animal models have been developed to gain insight into the pathogenesis associated with aerosolized [...] Read more.
Rift Valley fever virus (RVFV) is an emerging pathogen capable of causing severe disease in livestock and humans and can be transmitted by multiple routes including aerosol exposure. Several animal models have been developed to gain insight into the pathogenesis associated with aerosolized RVFV infection, but work with these models is restricted to high containment biosafety level (BSL) laboratories limiting their use for antiviral and vaccine development studies. Here, we report on a new RVFV inhalation infection model in STAT2 KO hamsters exposed to aerosolized MP-12 vaccine virus by nose-only inhalation that enables a more accurate delivery and measurement of exposure dose. RVFV was detected in hepatic and other tissues 4–5 days after challenge, consistent with virus-induced lesions in the liver, spleen and lung. Furthermore, assessment of blood chemistry and hematological parameters revealed alterations in several liver disease markers and white blood cell parameters. Our results indicate that STAT2 KO hamsters develop a disease course that shares features of disease observed in human cases and in other animal models of RVFV aerosol exposure, supporting the use of this BSL-2 infection model for countermeasure development efforts. Full article
(This article belongs to the Special Issue Animal Models for Viral Diseases)
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18 pages, 5572 KiB  
Article
Canine Influenza Virus is Mildly Restricted by Canine Tetherin Protein
by Yun Zheng, Xiangqi Hao, Qingxu Zheng, Xi Lin, Xin Zhang, Weijie Zeng, Shiyue Ding, Pei Zhou and Shoujun Li
Viruses 2018, 10(10), 565; https://doi.org/10.3390/v10100565 - 16 Oct 2018
Cited by 3 | Viewed by 3297
Abstract
Tetherin (BST2/CD317/HM1.24) has emerged as a key host-cell ·defence molecule that acts by inhibiting the release and spread of diverse enveloped virions from infected cells. We analysed the biological features of canine tetherin and found it to be an unstable hydrophilic type I [...] Read more.
Tetherin (BST2/CD317/HM1.24) has emerged as a key host-cell ·defence molecule that acts by inhibiting the release and spread of diverse enveloped virions from infected cells. We analysed the biological features of canine tetherin and found it to be an unstable hydrophilic type I transmembrane protein with one transmembrane domain, no signal peptide, and multiple glycosylation and phosphorylation sites. Furthermore, the tissue expression profile of canine tetherin revealed that it was particularly abundant in immune organs. The canine tetherin gene contains an interferon response element sequence that can be regulated and expressed by canine IFN-α. A CCK-8 assay showed that canine tetherin was effective in helping mitigate cellular damage caused by canine influenza virus (CIV) infection. Additionally, we found that the overexpression of canine tetherin inhibited replication of the CIV and that interference with the canine tetherin gene enhanced CIV replication in cells. The impact of canine tetherin on CIV replication was mild. However, these results elucidate the role of the innate immune factor, canine tetherin, during CIV infection for the first time. Full article
(This article belongs to the Special Issue Animal Models for Viral Diseases)
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14 pages, 1478 KiB  
Article
Transcript Profiling Identifies Early Response Genes against FMDV Infection in PK-15 Cells
by Tianliang Zhang, Haotai Chen, Linlin Qi, Jie Zhang, Run Wu, Yongguang Zhang and Yuefeng Sun
Viruses 2018, 10(7), 364; https://doi.org/10.3390/v10070364 - 11 Jul 2018
Cited by 16 | Viewed by 4230
Abstract
Foot-and-mouth disease (FMD) is a highly contagious disease that results in enormous economic loses worldwide. Although the protection provided by vaccination is limited during early infection, it is recognized as the best method to prevent FMD outbreaks. Furthermore, the mechanism of host early [...] Read more.
Foot-and-mouth disease (FMD) is a highly contagious disease that results in enormous economic loses worldwide. Although the protection provided by vaccination is limited during early infection, it is recognized as the best method to prevent FMD outbreaks. Furthermore, the mechanism of host early responses against foot-and-mouth disease virus (FMDV) infection remains unclear. In our study, a pig kidney cell line (PK-15) was used as a cell model to reveal the mechanism of early pig responses to FMDV infection. Four non-treated control and four FMDV-treated PK-15 cells were sequenced with RNA-seq technology, and the differentially expressed genes (DEGs) were analyzed. The results showed that 1212 DEGs were in the FMDV-infected PK-15 cells, including 914 up-regulated and 298 down-regulated genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were significantly enriched in the tumor necrosis factor (TNF), cytokine-cytokine receptor interaction, NOD-like receptor, toll-like receptor, NF-κB, and the chemokine signaling pathways. To verify the results of the DEGs, 30 immune-related DEGs (19 up-regulated and 11 down-regulated) were selected for Quantitative Reverse Transcriptase polymerase chain reaction (RT-qPCR) verification. The results showed that RT-qPCR-measured genes exhibited a similar pattern as the RNA-seq analyses. Based on bioinformatics analysis, during FMDV early infection, we found that a series of cytokines, such as interleukins (IL6), chemokines (CXCL2, CCL20 and CCL4), and transcription factors (ZFP36, FOS, NFKBIA, ZBTB3, ZNF503, ZNF283, dymeclin (DYM), and orthodenticle homeobox 1 (OTX1)) were involved in the battle between FMDV and the host. Combined with their features and functions, we propose inflammation as the main early mechanism by which the host responds to FMDV infection. These data provide an additional panel of candidate genes for deciphering the mechanisms of a host’s early response against FMDV infection. Full article
(This article belongs to the Special Issue Animal Models for Viral Diseases)
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14 pages, 3576 KiB  
Article
Cynomolgus Monkeys (Macaca fascicularis) as an Experimental Infection Model for Human Group A Rotavirus
by Gentil Arthur Bentes, Juliana Rodrigues Guimarães, Eduardo De Mello Volotão, Alexandre Madi Fialho, Cleber Hooper, Ana Carolina Ganime, Noemi Rovaris Gardinali, Natália Maria Lanzarini, Alexandre Dos Santos Da Silva, Jacob Pitcovski, José Paulo Leite and Marcelo Alves Pinto
Viruses 2018, 10(7), 355; https://doi.org/10.3390/v10070355 - 04 Jul 2018
Cited by 6 | Viewed by 3838
Abstract
Group A rotaviruses (RVA) are one of the most common causes of severe acute gastroenteritis in infants worldwide. Rotaviruses spread from person to person, mainly by faecal–oral transmission. Almost all unvaccinated children may become infected with RVA in the first two years of [...] Read more.
Group A rotaviruses (RVA) are one of the most common causes of severe acute gastroenteritis in infants worldwide. Rotaviruses spread from person to person, mainly by faecal–oral transmission. Almost all unvaccinated children may become infected with RVA in the first two years of life. The establishment of an experimental monkey model with RVA is important to evaluate new therapeutic approaches. In this study, we demonstrated viral shedding and viraemia in juvenile–adult Macaca fascicularis orally inoculated with Wa RVA prototype. Nine monkeys were inoculated orally: seven animals with human RVA and two control animals with saline solution. During the study, the monkeys were clinically monitored, and faeces and blood samples were tested for RVA infection. In general, the inoculated animals developed an oligosymptomatic infection pattern. The main clinical symptoms observed were diarrhoea in two monkeys for three days, associated with a reduction in plasmatic potassium content. Viral RNA was detected in seven faecal and five sera samples from inoculated animals, suggesting virus replication. Cynomolgus monkeys are susceptible hosts for human Wa RVA infection. When inoculated orally, they presented self-limited diarrhoea associated with presence of RVA infectious particles in faeces. Thus, cynomolgus monkeys may be useful as animal models to evaluate the efficacy of new antiviral approaches. Full article
(This article belongs to the Special Issue Animal Models for Viral Diseases)
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11 pages, 5402 KiB  
Article
Synergistic Viral Replication of Marek’s Disease Virus and Avian Leukosis Virus Subgroup J is Responsible for the Enhanced Pathogenicity in the Superinfection of Chickens
by Jing Zhou, Guo-Liang Zhao, Xiao-Man Wang, Xu-Sheng Du, Shuai Su, Chen-Gui Li, Venugopal Nair, Yong-Xiu Yao and Zi-Qiang Cheng
Viruses 2018, 10(5), 271; https://doi.org/10.3390/v10050271 - 18 May 2018
Cited by 14 | Viewed by 5925
Abstract
Superinfection of Marek’s disease virus (MDV) and avian leukosis virus subgroup J (ALV-J) causes lethal neoplasia and death in chickens. However, whether there is synergism between the two viruses in viral replication and pathogenicity has remained elusive. In this study, we found that [...] Read more.
Superinfection of Marek’s disease virus (MDV) and avian leukosis virus subgroup J (ALV-J) causes lethal neoplasia and death in chickens. However, whether there is synergism between the two viruses in viral replication and pathogenicity has remained elusive. In this study, we found that the superinfection of MDV and ALV-J increased the viral replication of the two viruses in RNA and protein level, and synergistically promoted the expression of IL-10, IL-6, and TGF-β in chicken embryo fibroblasts (CEF). Moreover, MDV and ALV-J protein expression in dual-infected cells detected by confocal laser scanning microscope appeared earlier in the cytoplasm and the nucleus, and caused more severe cytopathy than single infection, suggesting that synergistically increased MDV and ALV-J viral-protein biosynthesis is responsible for the severe cytopathy. In vivo, compared to the single virus infected chickens, the mortality and tumor formation rates increased significantly in MDV and ALV-J dual-infected chickens. Viral loads of MDV and ALV-J in tissues of dual-infected chickens were significantly higher than those of single-infected chickens. Histopathology observation showed that more severe inflammation and tumor cells metastases were present in dual-infected chickens. In the present study, we concluded that synergistic viral replication of MDV and ALV-J is responsible for the enhanced pathogenicity in superinfection of chickens. Full article
(This article belongs to the Special Issue Animal Models for Viral Diseases)
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14 pages, 2504 KiB  
Article
Avian Influenza Virus Subtype H9N2 Affects Intestinal Microbiota, Barrier Structure Injury, and Inflammatory Intestinal Disease in the Chicken Ileum
by Hongxin Li, Xiaolin Liu, Feiyang Chen, Kejing Zuo, Che Wu, Yiming Yan, Weiguo Chen, Wencheng Lin and Qingmei Xie
Viruses 2018, 10(5), 270; https://doi.org/10.3390/v10050270 - 18 May 2018
Cited by 52 | Viewed by 7139
Abstract
Avian influenza virus subtype H9N2 (H9N2 AIV) has caused significant losses to the poultry industry due to the high mortality associated with secondary infections attributable to E. coli. This study tries to address the underlying secondary mechanisms after H9N2 AIV infection. Initially, [...] Read more.
Avian influenza virus subtype H9N2 (H9N2 AIV) has caused significant losses to the poultry industry due to the high mortality associated with secondary infections attributable to E. coli. This study tries to address the underlying secondary mechanisms after H9N2 AIV infection. Initially, nine day-old specific pathogen-free chickens were assigned to control (uninfected) and H9N2-infected groups, respectively. Using Illumina sequencing, histological examination, and quantitative real-time PCR, it was found that H9N2 AIV caused intestinal microbiota disorder, injury, and inflammatory damage to the intestinal mucosa. Notably, the genera Escherichia, especially E. coli, significantly increased (p < 0.01) at five days post-infection (dpi), while Lactobacillus, Enterococcus, and other probiotic organisms were significantly reduced (p < 0.01). Simultaneously, the mRNA expression of tight junction proteins (ZO-1, claudin 3, and occludin), TFF2, and Muc2 were significantly reduced (p < 0.01), indicating the destruction of the intestinal epithelial cell tight junctions and the damage of mucin layer construction. Moreover, the mRNA expression of proinflammatory cytokines IFN-γ, IL-22, IFN-α, and IL-17A in intestinal epithelial cells were significantly upregulated, resulting in the inflammatory response and intestinal injury. Our findings may provide a theoretical basis for observed gastroenteritis-like symptoms such as diarrhea and secondary E. coli infection following H9N2 AIV infection. Full article
(This article belongs to the Special Issue Animal Models for Viral Diseases)
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Review

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22 pages, 1322 KiB  
Review
Recent Updates on Mouse Models for Human Immunodeficiency, Influenza, and Dengue Viral Infections
by Vinodhini Krishnakumar, Siva Sundara Kumar Durairajan, Kalichamy Alagarasu, Min Li and Aditya Prasad Dash
Viruses 2019, 11(3), 252; https://doi.org/10.3390/v11030252 - 13 Mar 2019
Cited by 18 | Viewed by 5600
Abstract
Well-developed mouse models are important for understanding the pathogenesis and progression of immunological response to viral infections in humans. Moreover, to test vaccines, anti-viral drugs and therapeutic agents, mouse models are fundamental for preclinical investigations. Human viruses, however, seldom infect mice due to [...] Read more.
Well-developed mouse models are important for understanding the pathogenesis and progression of immunological response to viral infections in humans. Moreover, to test vaccines, anti-viral drugs and therapeutic agents, mouse models are fundamental for preclinical investigations. Human viruses, however, seldom infect mice due to differences in the cellular receptors used by the viruses for entry, as well as in the innate immune responses in mice and humans. In other words, a species barrier exists when using mouse models for investigating human viral infections. Developing transgenic (Tg) mice models expressing the human genes coding for viral entry receptors and knock-out (KO) mice models devoid of components involved in the innate immune response have, to some extent, overcome this barrier. Humanized mouse models are a third approach, developed by engrafting functional human cells and tissues into immunodeficient mice. They are becoming indispensable for analyzing human viral diseases since they nearly recapitulate the human disease. These mouse models also serve to test the efficacy of vaccines and antiviral agents. This review provides an update on the Tg, KO, and humanized mouse models that are used in studies investigating the pathogenesis of three important human-specific viruses, namely human immunodeficiency (HIV) virus 1, influenza, and dengue. Full article
(This article belongs to the Special Issue Animal Models for Viral Diseases)
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18 pages, 2618 KiB  
Review
Mastomys Species as Model Systems for Infectious Diseases
by Daniel Hasche and Frank Rösl
Viruses 2019, 11(2), 182; https://doi.org/10.3390/v11020182 - 21 Feb 2019
Cited by 19 | Viewed by 5561
Abstract
Replacements of animal models by advanced in vitro systems in biomedical research, despite exceptions, are currently still not satisfactory in reproducing the whole complexity of pathophysiological mechanisms that finally lead to disease. Therefore, preclinical models are additionally required to reflect analogous in vivo [...] Read more.
Replacements of animal models by advanced in vitro systems in biomedical research, despite exceptions, are currently still not satisfactory in reproducing the whole complexity of pathophysiological mechanisms that finally lead to disease. Therefore, preclinical models are additionally required to reflect analogous in vivo situations as found in humans. Despite proven limitations of both approaches, only a combined experimental arrangement guarantees generalizability of results and their transfer to the clinics. Although the laboratory mouse still stands as a paradigm for many scientific discoveries and breakthroughs, it is mandatory to broaden our view by also using nontraditional animal models. The present review will first reflect the value of experimental systems in life science and subsequently describes the preclinical rodent model Mastomys coucha that—although still not well known in the scientific community—has a long history in research of parasites, bacteria, papillomaviruses and cancer. Using Mastomys, we could recently show for the first time that cutaneous papillomaviruses—in conjunction with UV as an environmental risk factor—induce squamous cell carcinomas of the skin via a “hit-and-run” mechanism. Moreover, Mastomys coucha was also used as a proof-of-principle model for the successful vaccination against non-melanoma skin cancer even under immunosuppressive conditions. Full article
(This article belongs to the Special Issue Animal Models for Viral Diseases)
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14 pages, 1096 KiB  
Review
Mouse Models Reveal Role of T-Cytotoxic and T-Reg Cells in Immune Response to Influenza: Implications for Vaccine Design
by Stewart Sell, Karl Kai McKinstry and Tara M. Strutt
Viruses 2019, 11(1), 52; https://doi.org/10.3390/v11010052 - 11 Jan 2019
Cited by 6 | Viewed by 4433
Abstract
Immunopathologic examination of the lungs of mouse models of experimental influenza virus infection provides new insights into the immune response in this disease. First, there is rapidly developing perivascular and peribronchial infiltration of the lung with T-cells. This is followed by invasion of [...] Read more.
Immunopathologic examination of the lungs of mouse models of experimental influenza virus infection provides new insights into the immune response in this disease. First, there is rapidly developing perivascular and peribronchial infiltration of the lung with T-cells. This is followed by invasion of T-cells into the bronchiolar epithelium, and separation of epithelial cells from each other and from the basement membrane leading to defoliation of the bronchial epithelium. The intraepithelial reaction may involve either CD8 or CD4 T-cytotoxic cells and is analogous to a viral exanthema of the skin, such as measles and smallpox, which occur when the immune response against these infections is activated and the infected cells are attacked by T-cytotoxic cells. Then there is formation of B-cell follicles adjacent to bronchi, i.e., induced bronchial associated lymphoid tissue (iBALT). iBALT reacts like the cortex of a lymph node and is a site for a local immune response not only to the original viral infection, but also related viral infections (heterologous immunity). Proliferation of Type II pneumocytes and/or terminal bronchial epithelial cells may extend into the adjacent lung leading to large zones filled with tumor-like epithelial cells. The effective killing of influenza virus infected epithelial cells by T-cytotoxic cells and induction of iBALT suggests that adding the induction of these components might greatly increase the efficacy of influenza vaccination. Full article
(This article belongs to the Special Issue Animal Models for Viral Diseases)
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25 pages, 858 KiB  
Review
Modeling Arboviral Infection in Mice Lacking the Interferon Alpha/Beta Receptor
by Alejandro Marín-Lopez, Eva Calvo-Pinilla, Sandra Moreno, Sergio Utrilla-Trigo, Aitor Nogales, Alejandro Brun, Erol Fikrig and Javier Ortego
Viruses 2019, 11(1), 35; https://doi.org/10.3390/v11010035 - 08 Jan 2019
Cited by 23 | Viewed by 5564
Abstract
Arboviruses are arthropod-borne viruses that exhibit worldwide distribution and are a constant threat, not only for public health but also for wildlife, domestic animals, and even plants. To study disease pathogenesis and to develop efficient and safe therapies, the use of an appropriate [...] Read more.
Arboviruses are arthropod-borne viruses that exhibit worldwide distribution and are a constant threat, not only for public health but also for wildlife, domestic animals, and even plants. To study disease pathogenesis and to develop efficient and safe therapies, the use of an appropriate animal model is a critical concern. Adult mice with gene knockouts of the interferon α/β (IFN-α/β) receptor (IFNAR(−/−)) have been described as a model of arbovirus infections. Studies with the natural hosts of these viruses are limited by financial and ethical issues, and in some cases, the need to have facilities with a biosafety level 3 with sufficient space to accommodate large animals. Moreover, the number of animals in the experiments must provide results with statistical significance. Recent advances in animal models in the last decade among other gaps in knowledge have contributed to the better understanding of arbovirus infections. A tremendous advantage of the IFNAR(−/−) mouse model is the availability of a wide variety of reagents that can be used to study many aspects of the immune response to the virus. Although extrapolation of findings in mice to natural hosts must be done with care due to differences in the biology between mouse and humans, experimental infections of IFNAR(−/−) mice with several studied arboviruses closely mimics hallmarks of these viruses in their natural host. Therefore, IFNAR(−/−) mice are a good model to facilitate studies on arbovirus transmission, pathogenesis, virulence, and the protective efficacy of new vaccines. In this review article, the most important arboviruses that have been studied using the IFNAR(−/−) mouse model will be reviewed. Full article
(This article belongs to the Special Issue Animal Models for Viral Diseases)
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13 pages, 1790 KiB  
Review
A ‘Furry-Tale’ of Zika Virus Infection: What Have We Learned from Animal Models?
by Loulieta Nazerai, Jan Pravsgaard Christensen and Allan Randrup Thomsen
Viruses 2019, 11(1), 29; https://doi.org/10.3390/v11010029 - 06 Jan 2019
Cited by 19 | Viewed by 7171
Abstract
The worldwide attention that the Zika virus (ZIKV) attracted, following its declaration as a Public Health Emergency of International concern by WHO in 2016, has led to a large collective effort by the international scientific community to understand its biology. Despite the mild [...] Read more.
The worldwide attention that the Zika virus (ZIKV) attracted, following its declaration as a Public Health Emergency of International concern by WHO in 2016, has led to a large collective effort by the international scientific community to understand its biology. Despite the mild symptoms caused by ZIKV in most infected people, the virus displays a number of worrying features, such as its ability to cause transplacental infection, fetal abnormalities and vector independent transmission through body fluids. In addition, the virus has been associated with the induction of Guillain-Barre syndrome in a number of infected individuals. With travelling, the virus has spread outside the original ZIKV endemic areas making it imperative to find ways to control it. Thus far, the large number of animal models developed to study ZIKV pathogenesis have proven to be valuable tools in understanding how the virus replicates and manifests itself in the host, its tissue tropism and the type of immune responses it induces. Still, vital questions, such as the molecular mechanisms of ZIKV persistence and the long-term consequences of ZIKV infection in the developing brain, remain unanswered. Here, we reviewed and discussed the major and most recent findings coming from animal studies and their implications for a ZIKV vaccine design. Full article
(This article belongs to the Special Issue Animal Models for Viral Diseases)
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23 pages, 2600 KiB  
Review
Mouse Model of Cytomegalovirus Disease and Immunotherapy in the Immunocompromised Host: Predictions for Medical Translation that Survived the “Test of Time”
by Matthias J. Reddehase and Niels A. W. Lemmermann
Viruses 2018, 10(12), 693; https://doi.org/10.3390/v10120693 - 06 Dec 2018
Cited by 64 | Viewed by 5549
Abstract
Human Cytomegalovirus (hCMV), which is the prototype member of the β-subfamily of the herpesvirus family, is a pathogen of high clinical relevance in recipients of hematopoietic cell transplantation (HCT). hCMV causes multiple-organ disease and interstitial pneumonia in particular upon infection during the immunocompromised [...] Read more.
Human Cytomegalovirus (hCMV), which is the prototype member of the β-subfamily of the herpesvirus family, is a pathogen of high clinical relevance in recipients of hematopoietic cell transplantation (HCT). hCMV causes multiple-organ disease and interstitial pneumonia in particular upon infection during the immunocompromised period before hematopoietic reconstitution restores antiviral immunity. Clinical investigation of pathomechanisms and of strategies for an immune intervention aimed at restoring antiviral immunity earlier than by hematopoietic reconstitution are limited in patients to observational studies mainly because of ethical issues including the imperative medical indication for chemotherapy with antivirals. Aimed experimental studies into mechanisms, thus, require animal models that match the human disease as close as possible. Any model for hCMV disease is, however, constrained by the strict host-species specificity of CMVs that prevents the study of hCMV in any animal model including non-human primates. During eons of co-speciation, CMVs each have evolved a set of “private genes” in adaptation to their specific mammalian host including genes that have no homolog in the CMV virus species of any other host species. With a focus on the mouse model of CD8 T cell-based immunotherapy of CMV disease after experimental HCT and infection with murine CMV (mCMV), we review data in support of the phenomenon of “biological convergence” in virus-host adaptation. This includes shared fundamental principles of immune control and immune evasion, which allows us to at least make reasoned predictions from the animal model as an experimental “proof of concept.” The aim of a model primarily is to define questions to be addressed by clinical investigation for verification, falsification, or modification and the results can then give feedback to refine the experimental model for research from “bedside to bench”. Full article
(This article belongs to the Special Issue Animal Models for Viral Diseases)
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37 pages, 1637 KiB  
Review
Small Animal Models of Respiratory Viral Infection Related to Asthma
by Mingyuan Han, Charu Rajput, Tomoko Ishikawa, Caitlin R. Jarman, Julie Lee and Marc B. Hershenson
Viruses 2018, 10(12), 682; https://doi.org/10.3390/v10120682 - 01 Dec 2018
Cited by 23 | Viewed by 8099
Abstract
Respiratory viral infections are strongly associated with asthma exacerbations. Rhinovirus is most frequently-detected pathogen; followed by respiratory syncytial virus; metapneumovirus; parainfluenza virus; enterovirus and coronavirus. In addition; viral infection; in combination with genetics; allergen exposure; microbiome and other pathogens; may play a role [...] Read more.
Respiratory viral infections are strongly associated with asthma exacerbations. Rhinovirus is most frequently-detected pathogen; followed by respiratory syncytial virus; metapneumovirus; parainfluenza virus; enterovirus and coronavirus. In addition; viral infection; in combination with genetics; allergen exposure; microbiome and other pathogens; may play a role in asthma development. In particular; asthma development has been linked to wheezing-associated respiratory viral infections in early life. To understand underlying mechanisms of viral-induced airways disease; investigators have studied respiratory viral infections in small animals. This report reviews animal models of human respiratory viral infection employing mice; rats; guinea pigs; hamsters and ferrets. Investigators have modeled asthma exacerbations by infecting mice with allergic airways disease. Asthma development has been modeled by administration of virus to immature animals. Small animal models of respiratory viral infection will identify cell and molecular targets for the treatment of asthma. Full article
(This article belongs to the Special Issue Animal Models for Viral Diseases)
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20 pages, 517 KiB  
Review
Immunocompetent and Immunodeficient Mouse Models for Enterovirus 71 Pathogenesis and Therapy
by Chiaho Shih, Chun-Che Liao, Ya-Shu Chang, Szu-Yao Wu, Chih-Shin Chang and An-Ting Liou
Viruses 2018, 10(12), 674; https://doi.org/10.3390/v10120674 - 28 Nov 2018
Cited by 32 | Viewed by 5124
Abstract
Enterovirus 71 (EV71) is a global health threat. Children infected with EV71 could develop hand-foot-and-mouth disease (HFMD), encephalitis, paralysis, pulmonary edema, and death. At present, no effective treatment for EV71 is available. We reviewed here various mouse models for EV71 pathogenesis and therapy. [...] Read more.
Enterovirus 71 (EV71) is a global health threat. Children infected with EV71 could develop hand-foot-and-mouth disease (HFMD), encephalitis, paralysis, pulmonary edema, and death. At present, no effective treatment for EV71 is available. We reviewed here various mouse models for EV71 pathogenesis and therapy. Earlier studies relied on the use of mouse-adapted EV71 strains. To avoid artificial mutations arising de novo during the serial passages, recent studies used EV71 clinical isolates without adaptation. Several human receptors for EV71 were shown to facilitate viral entry in cell culture. However, in vivo infection with human SCARB2 receptor transgenic mice appeared to be more limited to certain strains and genotypes of EV71. Efficacy of oral infection in these transgenic models is extremely low. Intriguingly, despite the lack of human receptors, immunodeficient neonatal mouse models can still be infected with EV71 clinical isolates via oral or intraperitoneal routes. Crossbreeding between SCARB2 transgenic and stat1 knockout mice generated a more sensitive and user-friendly hybrid mouse model. Infected hybrid mice developed a higher incidence and earlier onset of CNS disease and death. Different pathogenesis profiles were observed in models deficient in various arms of innate or humoral immunity. These models are being actively used for antiviral research. Full article
(This article belongs to the Special Issue Animal Models for Viral Diseases)
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17 pages, 265 KiB  
Review
Humanized Mouse Models for the Study of Infection and Pathogenesis of Human Viruses
by Fritz Lai and Qingfeng Chen
Viruses 2018, 10(11), 643; https://doi.org/10.3390/v10110643 - 17 Nov 2018
Cited by 20 | Viewed by 4457
Abstract
The evolution of infectious pathogens in humans proved to be a global health problem. Technological advancements over the last 50 years have allowed better means of identifying novel therapeutics to either prevent or combat these infectious diseases. The development of humanized mouse models [...] Read more.
The evolution of infectious pathogens in humans proved to be a global health problem. Technological advancements over the last 50 years have allowed better means of identifying novel therapeutics to either prevent or combat these infectious diseases. The development of humanized mouse models offers a preclinical in vivo platform for further characterization of human viral infections and human immune responses triggered by these virus particles. Multiple strains of immunocompromised mice reconstituted with a human immune system and/or human hepatocytes are susceptible to infectious pathogens as evidenced by establishment of full viral life cycles in hope of investigating viral–host interactions observed in patients and discovering potential immunotherapies. This review highlights recent progress in utilizing humanized mice to decipher human specific immune responses against viral tropism. Full article
(This article belongs to the Special Issue Animal Models for Viral Diseases)
7 pages, 469 KiB  
Review
Non-Human Primate Models of Enteric Viral Infections
by Karol Sestak
Viruses 2018, 10(10), 544; https://doi.org/10.3390/v10100544 - 05 Oct 2018
Cited by 6 | Viewed by 4508
Abstract
There is an important role non-human primates (NHP) play in biomedical research. Phylogenetic proximity of any of the NHP species to Homo sapiens assures that much better translatability of research outcomes from model studies involving human diseases can be achieved than from those [...] Read more.
There is an important role non-human primates (NHP) play in biomedical research. Phylogenetic proximity of any of the NHP species to Homo sapiens assures that much better translatability of research outcomes from model studies involving human diseases can be achieved than from those generated with other pre-clinical systems. Our group and others used during past two decades NHPs in research directed towards viral and autoimmune disorders of the gastrointestinal tract. This review summarizes progress made in the area of enteric viral infections including its applicability to human disease. Full article
(This article belongs to the Special Issue Animal Models for Viral Diseases)
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