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Pathogens
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Animal Models for Human Viruses
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Animal Models for Human Viruses

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

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 12532

Special Issue Editors

Prof. Dr. Carsten Münk

E-Mail Website
Guest Editor
Clinic for Gastroenterology, Hepatology and Infectiology, Medical Faculty, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany
Interests: HIV; retroviruses; restriction factors; innate sensing; antiviral deaminases
Special Issues, Collections and Topics in MDPI journals
Dr. Hanna-Mari Baldauf

E-Mail Website
Guest Editor
Max von Pettenkofer-Institute & Gene Center, Virology Medical Faculty, LMU München, 81377 Munich, Germany
Interests: viral infection; animal models

Special Issue Information

Dear Colleagues,

Many virus infections in humans do not need an animal as an in-between host. Other viruses in humans can have a zoonotic origin. Viruses may have a wide host range or a very narrow species or cell tropism. After spillover of animal viruses to humans, virus replication in humans is often blocked or limited, and these humans represent dead-end host. However, virus adaption over the time may generate true human viruses.

Animal models for human viruses deal with the delicate virus tropism and adaptation to human systems. For some viruses, the animal host may very well support virus spread and replication, while others may need genetic changes in the animal host, adaptions to host-cell factors or hybrid models in which human cells are transplanted into an animal to give the virus a suitable environment. Animal models for human viruses are needed to describe basic questions about cellular replication pathways, mechanism of latency, tissue reservoirs, and are of importance in investigating antiviral drugs, vaccines or any other preventive technique to inhibit virus spread or replication. This Special Issue of Pathogens welcomes reviews and articles reporting original data.

Prof. Dr. Carsten Münk
Dr. Hanna-Mari Baldauf
Guest Editors

Manuscript Submission Information

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

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.

Published Papers (6 papers)

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Research

Jump to: Review

21 pages, 5354 KiB  
Article
Newly Designed Poxviral Promoters to Improve Immunogenicity and Efficacy of MVA-NP Candidate Vaccines against Lethal Influenza Virus Infection in Mice
by Martin C. Langenmayer, Anna-Theresa Luelf-Averhoff, Lisa Marr, Sylvia Jany, Astrid Freudenstein, Silvia Adam-Neumair, Alina Tscherne, Robert Fux, Juan J. Rojas, Andreas Blutke, Gerd Sutter and Asisa Volz
Pathogens 2023, 12(7), 867; https://doi.org/10.3390/pathogens12070867 - 23 Jun 2023
Cited by 2 | Viewed by 1236
Abstract
Influenza, a respiratory disease mainly caused by influenza A and B, viruses of the Orthomyxoviridae, is still a burden on our society’s health and economic system. Influenza A viruses (IAV) circulate in mammalian and avian populations, causing seasonal outbreaks with high numbers [...] Read more.
Influenza, a respiratory disease mainly caused by influenza A and B, viruses of the Orthomyxoviridae, is still a burden on our society’s health and economic system. Influenza A viruses (IAV) circulate in mammalian and avian populations, causing seasonal outbreaks with high numbers of cases. Due to the high variability in seasonal IAV triggered by antigenic drift, annual vaccination is necessary, highlighting the need for a more broadly protective vaccine against IAV. The safety tested Modified Vaccinia virus Ankara (MVA) is licensed as a third-generation vaccine against smallpox and serves as a potent vector system for the development of new candidate vaccines against different pathogens. Here, we generated and characterized recombinant MVA candidate vaccines that deliver the highly conserved internal nucleoprotein (NP) of IAV under the transcriptional control of five newly designed chimeric poxviral promoters to further increase the immunogenic properties of the recombinant viruses (MVA-NP). Infections of avian cell cultures with the recombinant MVA-NPs demonstrated efficient synthesis of the IAV-NP which was expressed under the control of the five new promoters. Prime-boost or single shot immunizations in C57BL/6 mice readily induced circulating serum antibodies’ binding to recombinant IAV-NP and the robust activation of IAV-NP-specific CD8+ T cell responses. Moreover, the MVA-NP candidate vaccines protected C57BL/6 mice against lethal respiratory infection with mouse-adapted IAV (A/Puerto Rico/8/1934/H1N1). Thus, further studies are warranted to evaluate the immunogenicity and efficacy of these recombinant MVA-NP vaccines in other IAV challenge models in more detail. Full article
(This article belongs to the Special Issue Animal Models for Human Viruses)
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21 pages, 4494 KiB  
Article
Individual Epitope-Specific CD8+ T Cell Immune Responses Are Shaped Differently during Chronic Viral Infection
by Sebastian Klein, Jasmin Mischke, Finn Beruldsen, Immo Prinz, Dinler A. Antunes, Markus Cornberg and Anke R. M. Kraft
Pathogens 2023, 12(5), 716; https://doi.org/10.3390/pathogens12050716 - 14 May 2023
Viewed by 1486
Abstract
A hallmark in chronic viral infections are exhausted antigen-specific CD8+ T cell responses and the inability of the immune system to eliminate the virus. Currently, there is limited information on the variability of epitope-specific T cell exhaustion within one immune response and [...] Read more.
A hallmark in chronic viral infections are exhausted antigen-specific CD8+ T cell responses and the inability of the immune system to eliminate the virus. Currently, there is limited information on the variability of epitope-specific T cell exhaustion within one immune response and the relevance to the T cell receptor (TCR) repertoire. The aim of this study was a comprehensive analysis and comparison of three lymphocytic choriomeningitis virus (LCMV) epitope-specific CD8+ T cell responses (NP396, GP33 and NP205) in a chronic setting with immune intervention, e.g., immune checkpoint inhibitor (ICI) therapy, in regard to the TCR repertoire. These responses, though measured within the same mice, were individual and independent from each other. The massively exhausted NP396-specific CD8+ T cells revealed a significantly reduced TCR repertoire diversity, whereas less-exhausted GP33-specific CD8+ T cell responses were rather unaffected by chronicity in regard to their TCR repertoire diversity. NP205-specific CD8+ T cell responses showed a very special TCR repertoire with a prominent public motif of TCR clonotypes that was present in all NP205-specific responses, which separated this from NP396- and GP33-specific responses. Additionally, we showed that TCR repertoire shifts induced by ICI therapy are heterogeneous on the epitope level, by revealing profound effects in NP396-, less severe and opposed effects in NP205-, and minor effects in GP33-specific responses. Overall, our data revealed individual epitope-specific responses within one viral response that are differently affected by exhaustion and ICI therapy. These individual shapings of epitope-specific T cell responses and their TCR repertoires in an LCMV mouse model indicates important implications for focusing on epitope-specific responses in future evaluations for therapeutic approaches, e.g., for chronic hepatitis virus infections in humans. Full article
(This article belongs to the Special Issue Animal Models for Human Viruses)
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13 pages, 11458 KiB  
Article
Development of an Orthotopic HPV16-Dependent Base of Tongue Tumor Model in MHC-Humanized Mice
by Christoph Schifflers, Samantha Zottnick, Jonas D. Förster, Sebastian Kruse, Ruwen Yang, Hendrik Wiethoff, Matthias Bozza, Karin Hoppe-Seyler, Mathias Heikenwälder, Richard P. Harbottle, Carine Michiels and Angelika B. Riemer
Pathogens 2023, 12(2), 188; https://doi.org/10.3390/pathogens12020188 - 25 Jan 2023
Viewed by 1980
Abstract
Head and neck squamous cell carcinomas (HNSCC) caused by infections with high-risk human papillomaviruses (HPV) are responsible for an increasing number of head and neck cancers, particularly in the oropharynx. Despite the significant biological differences between HPV-driven and HPV-negative HNSCC, treatment strategies are [...] Read more.
Head and neck squamous cell carcinomas (HNSCC) caused by infections with high-risk human papillomaviruses (HPV) are responsible for an increasing number of head and neck cancers, particularly in the oropharynx. Despite the significant biological differences between HPV-driven and HPV-negative HNSCC, treatment strategies are similar and not HPV targeted. HPV-driven HNSCC are known to be more sensitive to treatment, particularly to radiotherapy, which is at least partially due to HPV-induced immunogenicity. The development of novel therapeutic strategies that are specific for HPV-driven cancers requires tumor models that reflect as closely as possible the characteristics and complexity of human tumors and their response to treatment. Current HPV-positive cancer models lack one or more hallmarks of their human counterpart. This study presents the development of a new HPV16 oncoprotein-dependent tumor model in MHC-humanized mice, modeling the major biologic features of HPV-driven tumors and presenting HLA-A2-restricted HPV16 epitopes. Furthermore, this model was developed to be orthotopic (base of tongue). Thus, it also reflects the correct tumor microenvironment of HPV-driven HNSCC. The cancer cells are implanted in a manner that allows the exact control of the anatomical location of the developing tumor, thereby homogenizing tumor growth. In conclusion, the new model is suited to study HPV16-specific therapeutic vaccinations and other immunotherapies, as well as tumor-targeted interventions, such as surgery or radiotherapy, or a combination of all these modalities. Full article
(This article belongs to the Special Issue Animal Models for Human Viruses)
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15 pages, 2289 KiB  
Article
Type I Interferon Signaling Controls Gammaherpesvirus Latency In Vivo
by Johannes Schwerk, Lucas Kemper, Kendra A. Bussey, Stefan Lienenklaus, Siegfried Weiss, Luka Čičin-Šain, Andrea Kröger, Ulrich Kalinke, Christopher M. Collins, Samuel H. Speck, Martin Messerle, Dagmar Wirth, Melanie M. Brinkmann, Hansjörg Hauser and Mario Köster
Pathogens 2022, 11(12), 1554; https://doi.org/10.3390/pathogens11121554 - 17 Dec 2022
Cited by 7 | Viewed by 1687
Abstract
Gammaherpesviruses, such as Epstein-Barr virus and Kaposi’s sarcoma-associated herpesvirus, are important human pathogens involved in lymphoproliferative disorders and tumorigenesis. Herpesvirus infections are characterized by a biphasic cycle comprised of an acute phase with lytic replication and a latent state. Murine gammaherpesvirus 68 (MHV-68) [...] Read more.
Gammaherpesviruses, such as Epstein-Barr virus and Kaposi’s sarcoma-associated herpesvirus, are important human pathogens involved in lymphoproliferative disorders and tumorigenesis. Herpesvirus infections are characterized by a biphasic cycle comprised of an acute phase with lytic replication and a latent state. Murine gammaherpesvirus 68 (MHV-68) is a well-established model for the study of lytic and latent life cycles in the mouse. We investigated the interplay between the type I interferon (IFN)-mediated innate immune response and MHV-68 latency using sensitive bioluminescent reporter mice. Adoptive transfer of latently infected splenocytes into type I IFN receptor-deficient mice led to a loss of latency control. This was revealed by robust viral propagation and dissemination of MHV-68, which coincided with type I IFN reporter induction. Despite MHV-68 latency control by IFN, the continuous low-level cell-to-cell transmission of MHV-68 was detected in the presence of IFN signaling, indicating that IFN cannot fully prevent viral dissemination during latency. Moreover, impaired type I IFN signaling in latently infected splenocytes increased the risk of virus reactivation, demonstrating that IFN directly controls MHV-68 latency in infected cells. Overall, our data show that locally constrained type I IFN responses control the cellular reservoir of latency, as well as the distribution of latent infection to potential new target cells. Full article
(This article belongs to the Special Issue Animal Models for Human Viruses)
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Review

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25 pages, 1237 KiB  
Review
Mouse Models for Human Herpesviruses
by Ivana Kutle, Anne Dittrich and Dagmar Wirth
Pathogens 2023, 12(7), 953; https://doi.org/10.3390/pathogens12070953 - 19 Jul 2023
Cited by 1 | Viewed by 2282
Abstract
More than one hundred herpesviruses have been isolated from different species so far, with nine infecting humans. Infections with herpesviruses are characterized by life-long latency and represent a significant challenge for human health. To investigate the consequences of infections and identify novel treatment [...] Read more.
More than one hundred herpesviruses have been isolated from different species so far, with nine infecting humans. Infections with herpesviruses are characterized by life-long latency and represent a significant challenge for human health. To investigate the consequences of infections and identify novel treatment options, in vivo models are of particular relevance. The mouse has emerged as an economical small animal model to investigate herpesvirus infections. However, except for herpes simplex viruses (HSV-1, HSV-2), human herpesviruses cannot infect mice. Three natural herpesviruses have been identified in mice: mouse-derived cytomegalovirus (MCMV), mouse herpesvirus 68 (MHV-68), and mouse roseolovirus (MRV). These orthologues are broadly used to investigate herpesvirus infections within the natural host. In the last few decades, immunocompromised mouse models have been developed, allowing the functional engraftment of various human cells and tissues. These xenograft mice represent valuable model systems to investigate human-restricted viruses, making them particularly relevant for herpesvirus research. In this review, we describe the various mouse models used to study human herpesviruses, thereby highlighting their potential and limitations. Emphasis is laid on xenograft mouse models, covering the development and refinement of immune-compromised mice and their application in herpesvirus research. Full article
(This article belongs to the Special Issue Animal Models for Human Viruses)
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23 pages, 831 KiB  
Review
The Humanized Mouse Model: What Added Value Does It Offer for HIV Research?
by Luca Baroncini, Simon Bredl, Kadzioch P. Nicole and Roberto F. Speck
Pathogens 2023, 12(4), 608; https://doi.org/10.3390/pathogens12040608 - 17 Apr 2023
Cited by 4 | Viewed by 3189
Abstract
In the early 2000s, novel humanized mouse models based on the transplantation of human hematopoietic stem and progenitor cells (HSPCs) into immunocompromised mice were introduced (hu mice). The human HSPCs gave rise to a lymphoid system of human origin. The HIV research community [...] Read more.
In the early 2000s, novel humanized mouse models based on the transplantation of human hematopoietic stem and progenitor cells (HSPCs) into immunocompromised mice were introduced (hu mice). The human HSPCs gave rise to a lymphoid system of human origin. The HIV research community has greatly benefitted from these hu mice. Since human immunodeficiency virus (HIV) type 1 infection results in a high-titer disseminated HIV infection, hu mice have been of great value for all types of HIV research from pathogenesis to novel therapies. Since the first description of this new generation of hu mice, great efforts have been expended to improve humanization by creating other immunodeficient mouse models or supplementing mice with human transgenes to improve human engraftment. Many labs have their own customized hu mouse models, making comparisons quite difficult. Here, we discuss the different hu mouse models in the context of specific research questions in order to define which characteristics should be considered when determining which hu mouse model is appropriate for the question posed. We strongly believe that researchers must first define their research question and then determine whether a hu mouse model exists, allowing the research question to be studied. Full article
(This article belongs to the Special Issue Animal Models for Human Viruses)
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