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Pathogens
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Comparative Animal Models of Human Viral Infections
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Comparative Animal Models of Human Viral Infections

A special issue of Pathogens (ISSN 2076-0817). This special issue belongs to the section "Viral Pathogens".

Deadline for manuscript submissions: closed (30 November 2023) | Viewed by 23102

Special Issue Editor

Prof. Dr. Hinh Ly

E-Mail Website
Guest Editor
Department of Veterinary & Biomedical Sciences, University of Minnesota, Twin Cities, MN, USA
Interests: hemorrhagic fever viruses; arenaviruses; lassa fever; host-virus interactions; innate immunity; viral pathogenesis and host defense
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Experimental animal modeling has long been a cornerstone for understanding the in vivo effects of virus infection, replication, and disease pathogenesis of a number of DNA and RNA viruses that infect humans. Over the years, conventional and unconventional animal models have been developed for this purpose. The goal of this Special Issue is to gather the latest information on recent advances in the development of animal models for understanding human viral infections and the diseases caused by them. Contributions in the form of primary research articles, reviews, mini-reviews, methods, and commentary/opinion articles are solicited from experts, who can provide an in-depth analysis of new or improved comparative animal models of virus-associated diseases in humans, including those caused by re/emerging zoonotic viruses. Topics include, but are not necessarily limited to (i) the effectiveness and/or challenges of using animal models to investigate the basic biology and disease pathogenesis of human viral infections; (ii) the development of new animal models for understanding human virus-associated disease pathologies; and (iii) new observations and/or future outlooks for animal model studies of human viral infections.

Thank you for your timely contributions.

Prof. Dr. Hinh Ly
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. Pathogens 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.

Keywords

  • animal models
  • infectious diseases
  • virus-associated immunological
  • hematological
  • neurological
  • hepatic
  • enteric
  • metabolic diseases
  • oncoviruses
  • arboviruses
  • respiratory viruses

Published Papers (8 papers)

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Editorial

Jump to: Research, Review

4 pages, 189 KiB  
Editorial
Comparative Animal Models of Human Viral Infections
by Hinh Ly
Pathogens 2022, 11(12), 1395; https://doi.org/10.3390/pathogens11121395 - 22 Nov 2022
Viewed by 999
Abstract
Comparative animal modeling has long served as a cornerstone for understanding the biological effects of infection by many DNA and RNA viruses [...] Full article
(This article belongs to the Special Issue Comparative Animal Models of Human Viral Infections)

Research

Jump to: Editorial, Review

13 pages, 5861 KiB  
Article
Volume-Associated Clinical and Histopathological Effects of Intranasal Instillation in Syrian Hamsters: Considerations for Infection and Therapeutic Studies
by Catalina Forero, Jana M. Ritter, Josilene Nascimento Seixas, JoAnn D. Coleman-McCray, Marie Brake, Jillian A. Condrey, Cassandra Tansey, Stephen R. Welch, Sarah C. Genzer and Jessica R. Spengler
Pathogens 2022, 11(8), 898; https://doi.org/10.3390/pathogens11080898 - 10 Aug 2022
Cited by 2 | Viewed by 1700
Abstract
Syrian hamsters are a key animal model of SARS-CoV-2 and other respiratory viruses and are useful for the evaluation of associated medical countermeasures. Delivery of an infectious agent or intervention to the respiratory tract mirrors natural routes of exposure and allows for the [...] Read more.
Syrian hamsters are a key animal model of SARS-CoV-2 and other respiratory viruses and are useful for the evaluation of associated medical countermeasures. Delivery of an infectious agent or intervention to the respiratory tract mirrors natural routes of exposure and allows for the evaluation of clinically relevant therapeutic administration. The data to support instillation or inoculation volumes are important both for optimal experimental design and to minimize or avoid effects of diluent alone, which may compromise both data interpretation and animal welfare. Here we investigate four intranasal (IN) instillation volumes in hamsters (50, 100, 200, or 400 µL). The animals were monitored daily, and a subset were serially euthanized at one of four pre-determined time-points (1, 3, 7, and 14 days post-instillation). Weight, temperature, oxygen saturation, CBC, radiographs, and respiratory tissue histopathology were assessed to determine changes associated with instillation volume alone. With all the delivery volumes, we found no notable differences between instilled and non-instilled controls in all of the parameters assessed, except for histopathology. In the animals instilled with 200 or 400 µL, inflammation associated with foreign material was detected in the lower respiratory tract indicating that higher volumes may result in aspiration of nasal and/or oropharyngeal material in a subset of animals, resulting in IN instillation-associated histopathology. Full article
(This article belongs to the Special Issue Comparative Animal Models of Human Viral Infections)
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15 pages, 1913 KiB  
Article
Three Immunocompetent Small Animal Models That Do Not Support Zika Virus Infection
by Megan R. Miller, Anna C. Fagre, Taylor C. Clarkson, Erin D. Markle and Brian D. Foy
Pathogens 2021, 10(8), 971; https://doi.org/10.3390/pathogens10080971 - 30 Jul 2021
Cited by 3 | Viewed by 1921
Abstract
Zika virus (ZIKV) is a mosquito-borne flavivirus that is primarily transmitted to humans through the bite of an infected mosquito. ZIKV causes disease in infected humans with added complications of Guillain-Barré syndrome and birth defects in infants born to mothers infected during pregnancy. [...] Read more.
Zika virus (ZIKV) is a mosquito-borne flavivirus that is primarily transmitted to humans through the bite of an infected mosquito. ZIKV causes disease in infected humans with added complications of Guillain-Barré syndrome and birth defects in infants born to mothers infected during pregnancy. There are several large immunocompetent animal models for ZIKV including non-human primates (NHPs). NHP models closely reflect human infection; however, due to sample size restrictions, investigations into the effects of transmission route and the impacts on disease dynamics have been understudied. Mice have been widely used for modeling ZIKV infection, yet there are few ZIKV-susceptible immunocompetent mouse models and none of these have been used to investigate sexual transmission. In an effort to identify a small immunocompetent animal model to characterize sexual transmission of ZIKV, we attempt experimental infection of multimammate mice, New Zealand white rabbits, and Hartley guinea pigs. The multimammate mouse is the natural reservoir of Lassa fever virus and has been identified to harbor other human pathogens. Likewise, while NZW rabbits are susceptible to West Nile virus, they have not yet been examined for their susceptibility to infection with ZIKV. Guinea pigs have been successfully used as models for ZIKV infection, but only in immunocompromised life stages (young or pregnant). Here, it was found that the multimammate mouse and New Zealand White (NZW) rabbits are not susceptible ZIKV infection as determined by a lack viral RNA in tissues and fluids collected. Sexually mature male Hartley guinea pigs were inoculated subcutaneously and by mosquito bite, but found to be refractory to ZIKV infection, contrary to findings of other studies in young and pregnant guinea pigs. Interestingly, here it is shown that adult male guinea pigs are not susceptible to ZIKV infection, even when infected by natural route (e.g., mosquito bite). Although a new small animal model for the sexual transmission for ZIKV was not established through this study, these findings provide information on outbred animal species that are not permissive to infection (NZW rabbits and multimammate mice) and new information surrounding limitations of a previously established animal model (guinea pigs). Full article
(This article belongs to the Special Issue Comparative Animal Models of Human Viral Infections)
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20 pages, 17315 KiB  
Article
Pichinde Virus Infection of Outbred Hartley Guinea Pigs as a Surrogate Animal Model for Human Lassa Fever: Histopathological and Immunohistochemical Analyses
by Wun-Ju Shieh, Shuiyun Lan, Sherif R. Zaki, Hinh Ly and Yuying Liang
Pathogens 2020, 9(7), 579; https://doi.org/10.3390/pathogens9070579 - 16 Jul 2020
Cited by 6 | Viewed by 3119
Abstract
Lassa virus (LASV) is a mammarenavirus (arenavirus) that causes zoonotic infection in humans that can lead to fatal hemorrhagic Lassa fever (LF) disease. Currently, there are no FDA-approved vaccines or therapeutics against LASV. Development of treatments against LF and other related arenavirus-induced hemorrhagic [...] Read more.
Lassa virus (LASV) is a mammarenavirus (arenavirus) that causes zoonotic infection in humans that can lead to fatal hemorrhagic Lassa fever (LF) disease. Currently, there are no FDA-approved vaccines or therapeutics against LASV. Development of treatments against LF and other related arenavirus-induced hemorrhagic fevers (AHFs) requires relevant animal models that can recapitulate clinical and pathological features of AHF diseases in humans. Laboratory mice are generally resistant to LASV infection, and non-human primates, while being a good animal model for LF, are limited by their high cost. Here, we describe a small, affordable, and convenient animal model that is based on outbred Hartley guinea pigs infected with Pichinde virus (PICV), a mammarenavirus that is non-pathogenic in humans, for use as a surrogate model of human LF. We conducted a detailed analysis of tissue histopathology and immunohistochemical analysis of different organs of outbred Hartley guinea pigs infected with different PICV strains that show differential disease phenotypes and pathologies. Comparing to infection with the avirulent PICV strain (P2 or rP2), animals infected with the virulent strain (P18 or rP18) show extensive pathological changes in different organs that sustain high levels of virus replication. The similarity of tissue pathology and viral antigen distribution between the virulent PICV–guinea pig model and lethal human LASV infection supports a role of this small animal model as a surrogate model of studying human LF in order to understand its pathogenesis and for evaluating potential preventative and therapeutic options against AHFs. Full article
(This article belongs to the Special Issue Comparative Animal Models of Human Viral Infections)
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17 pages, 1778 KiB  
Article
Vascular Leak and Hypercytokinemia Associated with Severe Fever with Thrombocytopenia Syndrome Virus Infection in Mice
by Jonna B. Westover, Brady T. Hickerson, Arnaud J. Van Wettere, Brett L. Hurst, Jacqueline P. Kurz, Ashley Dagley, Petra Wülfroth, Takashi Komeno, Yousuke Furuta, Thomas Steiner and Brian B. Gowen
Pathogens 2019, 8(4), 158; https://doi.org/10.3390/pathogens8040158 - 21 Sep 2019
Cited by 13 | Viewed by 3855
Abstract
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging viral hemorrhagic fever (VHF) endemic to China, South Korea, Japan, and Vietnam. Here we characterize the pathogenesis and natural history of disease in IFNAR-/- mice challenged with the HB29 strain of SFTS virus [...] Read more.
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging viral hemorrhagic fever (VHF) endemic to China, South Korea, Japan, and Vietnam. Here we characterize the pathogenesis and natural history of disease in IFNAR-/- mice challenged with the HB29 strain of SFTS virus (SFTSV) and demonstrate hallmark features of VHF such as vascular leak and high concentrations of proinflammatory cytokines in blood and tissues. Treatment with FX06, a natural plasmin digest product of fibrin in clinical development as a treatment for vascular leak, reduced vascular permeability associated with SFTSV infection but did not significantly improve survival outcome. Further studies are needed to assess the role of vascular compromise in the SFTS disease process modeled in IFNAR-/- mice. Full article
(This article belongs to the Special Issue Comparative Animal Models of Human Viral Infections)
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Review

Jump to: Editorial, Research

36 pages, 3850 KiB  
Review
Mice as an Animal Model for Japanese Encephalitis Virus Research: Mouse Susceptibility, Infection Route, and Viral Pathogenesis
by Jordan C. Frank, Byung-Hak Song and Young-Min Lee
Pathogens 2023, 12(5), 715; https://doi.org/10.3390/pathogens12050715 - 14 May 2023
Cited by 2 | Viewed by 2506
Abstract
Japanese encephalitis virus (JEV), a zoonotic flavivirus, is principally transmitted by hematophagous mosquitoes, continually between susceptible animals and incidentally from those animals to humans. For almost a century since its discovery, JEV was geographically confined to the Asia-Pacific region with recurrent sizable outbreaks [...] Read more.
Japanese encephalitis virus (JEV), a zoonotic flavivirus, is principally transmitted by hematophagous mosquitoes, continually between susceptible animals and incidentally from those animals to humans. For almost a century since its discovery, JEV was geographically confined to the Asia-Pacific region with recurrent sizable outbreaks involving wildlife, livestock, and people. However, over the past decade, it has been detected for the first time in Europe (Italy) and Africa (Angola) but has yet to cause any recognizable outbreaks in humans. JEV infection leads to a broad spectrum of clinical outcomes, ranging from asymptomatic conditions to self-limiting febrile illnesses to life-threatening neurological complications, particularly Japanese encephalitis (JE). No clinically proven antiviral drugs are available to treat the development and progression of JE. There are, however, several live and killed vaccines that have been commercialized to prevent the infection and transmission of JEV, yet this virus remains the main cause of acute encephalitis syndrome with high morbidity and mortality among children in the endemic regions. Therefore, significant research efforts have been directed toward understanding the neuropathogenesis of JE to facilitate the development of effective treatments for the disease. Thus far, multiple laboratory animal models have been established for the study of JEV infection. In this review, we focus on mice, the most extensively used animal model for JEV research, and summarize the major findings on mouse susceptibility, infection route, and viral pathogenesis reported in the past and present, and discuss some unanswered key questions for future studies. Full article
(This article belongs to the Special Issue Comparative Animal Models of Human Viral Infections)
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24 pages, 1092 KiB  
Review
Pathogen Dose in Animal Models of Hemorrhagic Fever Virus Infections and the Potential Impact on Studies of the Immune Response
by Bryce M. Warner
Pathogens 2021, 10(3), 275; https://doi.org/10.3390/pathogens10030275 - 01 Mar 2021
Cited by 3 | Viewed by 3020
Abstract
Viral hemorrhagic fever viruses come from a wide range of virus families and are a significant cause of morbidity and mortality worldwide each year. Animal models of infection with a number of these viruses have contributed to our knowledge of their pathogenesis and [...] Read more.
Viral hemorrhagic fever viruses come from a wide range of virus families and are a significant cause of morbidity and mortality worldwide each year. Animal models of infection with a number of these viruses have contributed to our knowledge of their pathogenesis and have been crucial for the development of therapeutics and vaccines that have been approved for human use. Most of these models use artificially high doses of virus, ensuring lethality in pre-clinical drug development studies. However, this can have a significant effect on the immune response generated. Here I discuss how the dose of antigen or pathogen is a critical determinant of immune responses and suggest that the current study of viruses in animal models should take this into account when developing and studying animal models of disease. This can have implications for determination of immune correlates of protection against disease as well as informing relevant vaccination and therapeutic strategies. Full article
(This article belongs to the Special Issue Comparative Animal Models of Human Viral Infections)
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19 pages, 679 KiB  
Review
Animal Models for Gammaherpesvirus Infections: Recent Development in the Analysis of Virus-Induced Pathogenesis
by Shigeyoshi Fujiwara and Hiroyuki Nakamura
Pathogens 2020, 9(2), 116; https://doi.org/10.3390/pathogens9020116 - 12 Feb 2020
Cited by 20 | Viewed by 4701
Abstract
Epstein–Barr virus (EBV) is involved in the pathogenesis of various lymphomas and carcinomas, whereas Kaposi’s sarcoma-associated herpesvirus (KSHV) participates in the pathogenesis of endothelial sarcoma and lymphomas. EBV and KSHV are responsible for 120,000 and 44,000 annual new cases of cancer, respectively. Despite [...] Read more.
Epstein–Barr virus (EBV) is involved in the pathogenesis of various lymphomas and carcinomas, whereas Kaposi’s sarcoma-associated herpesvirus (KSHV) participates in the pathogenesis of endothelial sarcoma and lymphomas. EBV and KSHV are responsible for 120,000 and 44,000 annual new cases of cancer, respectively. Despite this clinical importance, no chemotherapies or vaccines have been developed for virus-specific treatment and prevention of these viruses. Humans are the only natural host for both EBV and KSHV, and only a limited species of laboratory animals are susceptible to their experimental infection; this strict host tropism has hampered the development of their animal models and thereby impeded the study of therapeutic and prophylactic strategies. To overcome this difficulty, three main approaches have been used to develop animal models for human gammaherpesvirus infections. The first is experimental infection of laboratory animals with EBV or KSHV. New-world non-human primates (NHPs) and rabbits have been mainly used in this approach. The second is experimental infection of laboratory animals with their own inherent gammaherpesviruses. NHPs and mice have been mainly used here. The third, a recent trend, employs experimental infection of EBV or KSHV or both to immunodeficient mice reconstituted with human immune system components (humanized mice). This review will discuss how these three approaches have been used to reproduce human clinical conditions associated with gammaherpesviruses and to analyze the mechanisms of their pathogenesis. Full article
(This article belongs to the Special Issue Comparative Animal Models of Human Viral Infections)
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