Special Issue "In Vivo Mouse Models of Human Viral Infections"

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Human Virology and Viral Diseases".

Deadline for manuscript submissions: 22 December 2021.

Special Issue Editors

Prof. Charu Kaushic
E-Mail Website
Guest Editor
Department of Medicine, McMaster Immunolgy Research Center, McMaster University, Hamilton, Canada
Interests: HIV; HSV-2; mouse models of sexually transmitted infections; hormones; microbiome; mucosal immunology; sexually transmitted infections; women’s Reproductive health; in vitro host-pathogen models
Special Issues and Collections in MDPI journals
Dr. Amy Gillgrass
E-Mail Website
Guest Editor
Department of Medicine, McMaster Immunology Research Centre (MIRC), Institute for Infectious Disease Research (IIDR), McMaster University, Hamilton, Canada
Interests: humanized mice; infectious disease; HIV; TB; immunology; therapeutics; vaccines

Special Issue Information

Dear Colleagues,

The use of in vivo mouse models of human viral infections has been integral to advancing knowledge of these pathogens and diseases.  Mouse models of many human viral infections, including sexually transmitted viruses such as HIV and HSV-2, respiratory transmitted viruses such as Influenza and SARS-CoV2 and emerging infections such as ZIKA virus and EBOLA have laid the ground work for examining pathogenesis, therapeutics, vaccines, and immune responses.  As new pathogens emerge, researchers have responded by creating in vivo models to ask the questions that are challenging to study in human studies.  New innovations in in vivo models such as use of transgenic mice in Zika have been used to examine sexual transmission of this virus and its effects in pregnancy. Humanized mice have enabled the examination of HIV pathogenesis and therapeutics and rapid advances in these models are allowing investigation into more complex areas such as latency and vaccination.  For SARS-CoV2 in vivo mouse models have allowed for testing many of the vaccine candidates in challenge experiments and understand immune responses. 

In this issue, we hope to develop a collection of papers using mouse model systems to generate new knowledge about human viral infections. 

Prof. Charu Kaushic
Dr. Amy Gillgrass
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 papers will be 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. Viruses 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 2200 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

  • virus
  • in vivo
  • animal models
  • mouse models
  • HIV-1
  • HSV-2
  • ZIKA
  • influenza
  • SARS-CoV2
  • Ebola

Published Papers (5 papers)

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Research

Article
Morphological Aspects and Viremia Analysis of BALB/c Murine Model Experimentally Infected with Dengue Virus Serotype 4
Viruses 2021, 13(10), 1954; https://0-doi-org.brum.beds.ac.uk/10.3390/v13101954 - 29 Sep 2021
Viewed by 272
Abstract
Ever since its brief introduction in the Brazilian territory in 1981, dengue virus serotype 4 (DENV-4) remained absent from the national epidemiological scenario for almost 25 years. The emergence of DENV-4 in 2010 resulted in epidemics in most Brazilian states. DENV-4, however, remains [...] Read more.
Ever since its brief introduction in the Brazilian territory in 1981, dengue virus serotype 4 (DENV-4) remained absent from the national epidemiological scenario for almost 25 years. The emergence of DENV-4 in 2010 resulted in epidemics in most Brazilian states. DENV-4, however, remains one of the least studied among the four DENV serotypes. Despite being known as a mild serotype, DENV-4 is associated with severe cases and deaths and deserves to be investigated; however, the lack of suitable experimental animal models is a limiting factor for pathogenesis studies. Here, we aimed to investigate the susceptibility and potential tropism of DENV-4 for liver, lung and heart of an immunocompetent mice model, and to evaluate and investigate the resulting morphological and ultrastructural alterations upon viral infection. BALB/c mice were inoculated intravenously with non-neuroadapted doses of DENV-4 isolated from a human case. The histopathological analysis of liver revealed typical alterations of DENV, such as microsteatosis, edema and vascular congestion, while in lung, widespread areas of hemorrhage and interstitial pneumonia were observed. While milder alterations were present in heart, characterized by limited hemorrhage and discrete presence of inflammatory infiltrate, the disorganization of the structure of the intercalated disc is of particular interest. DENV-4 RNA was detected in liver, lung, heart and serum of BALB/c mice through qRT-PCR, while the NS3 viral protein was observed in all of the aforementioned organs through immunohistochemistry. These findings indicate the susceptibility of the model to the serotype and further reinforce the usefulness of BALB/c mice in studying the many alterations caused by DENV. Full article
(This article belongs to the Special Issue In Vivo Mouse Models of Human Viral Infections)
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Article
Primary HSV-2 Infection in Early Pregnancy Results in Transplacental Viral Transmission and Dose-Dependent Adverse Pregnancy Outcomes in a Novel Mouse Model
Viruses 2021, 13(10), 1929; https://0-doi-org.brum.beds.ac.uk/10.3390/v13101929 - 25 Sep 2021
Viewed by 395
Abstract
Herpes simplex virus type 2 (HSV-2) infection affects 24 million births annually and is associated with adverse pregnancy outcomes, including neonatal herpes; however, the mechanisms underlying in utero transmission of HSV-2 are largely unknown. We examined the effects of primary HSV-2 infection during [...] Read more.
Herpes simplex virus type 2 (HSV-2) infection affects 24 million births annually and is associated with adverse pregnancy outcomes, including neonatal herpes; however, the mechanisms underlying in utero transmission of HSV-2 are largely unknown. We examined the effects of primary HSV-2 infection during early pregnancy on gestational outcomes in a novel, clinically relevant mouse model. Pregnant C57BL/6 mice were infected intravaginally with 102–105 pfu/mL HSV-2 on gestation day (gd) 4.5. Controls were infected, nonpregnant, diestrus-staged mice and pregnant, uninfected mice. Compared to nonpregnant mice, pregnant mice were 100-fold more susceptible to HSV-2 infection. Three days post-inoculation (gd7.5), viral DNA was present in implantation sites, but pregnancy outcomes were largely unaffected by infection. Eight days post-inoculation (gd12.5), HSV-2 DNA persisted in placental tissues, resulting in inflammation and hemorrhage. Fetal and placental weights were reduced and fetal loss was observed with high viral doses. HSV-2 DNA and increased expression of pro-inflammatory mediators were detected in fetal tissues at gd12.5, signifying viral transmission and fetal infection, even with low viral doses. This mouse model shows a dose-dependent effect of primary HSV-2 infection on pregnancy outcomes and suggests that fetal loss may occur due to placental inflammation, thus providing valuable insight into in utero transmission of HSV-2. Full article
(This article belongs to the Special Issue In Vivo Mouse Models of Human Viral Infections)
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Article
Coxsackievirus A2 Leads to Heart Injury in a Neonatal Mouse Model
Viruses 2021, 13(8), 1588; https://0-doi-org.brum.beds.ac.uk/10.3390/v13081588 - 11 Aug 2021
Cited by 1 | Viewed by 580
Abstract
Coxsackievirus A2 (CVA2) has emerged as an active pathogen that has been implicated in hand, foot, and mouth disease (HFMD) and herpangina outbreaks worldwide. It has been reported that severe cases with CVA2 infection develop into heart injury, which may be one of [...] Read more.
Coxsackievirus A2 (CVA2) has emerged as an active pathogen that has been implicated in hand, foot, and mouth disease (HFMD) and herpangina outbreaks worldwide. It has been reported that severe cases with CVA2 infection develop into heart injury, which may be one of the causes of death. However, the mechanisms of CVA2-induced heart injury have not been well understood. In this study, we used a neonatal mouse model of CVA2 to investigate the possible mechanisms of heart injury. We detected CVA2 replication and apoptosis in heart tissues from infected mice. The activity of total aspartate transaminase (AST) and lactate dehydrogenase (LDH) was notably increased in heart tissues from infected mice. CVA2 infection also led to the disruption of cell-matrix interactions in heart tissues, including the increases of matrix metalloproteinase (MMP)3, MMP8, MMP9, connective tissue growth factor (CTGF) and tissue inhibitors of metalloproteinases (TIMP)4. Infiltrating leukocytes (CD45+ and CD11b+ cells) were observed in heart tissues of infected mice. Correspondingly, the expression levels of inflammatory cytokines in tissue lysates of hearts, including tumor necrosis factor alpha (TNF-α), interleukin-1beta (IL-1β), IL6 and monocyte chemoattractant protein-1 (MCP-1) were significantly elevated in CVA2 infected mice. Inflammatory signal pathways in heart tissues, including phosphatidylinositol 3-kinase (PI3K)-AKT, mitogen-activated protein kinases (MAPK) and nuclear factor kappa B (NF-κB), were also activated after infection. In summary, CVA2 infection leads to heart injury in a neonatal mouse model, which might be related to viral replication, increased expression levels of MMP-related enzymes and excessive inflammatory responses. Full article
(This article belongs to the Special Issue In Vivo Mouse Models of Human Viral Infections)
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Article
STAT-1 Knockout Mice as a Model for Wild-Type Sudan Virus (SUDV)
Viruses 2021, 13(7), 1388; https://0-doi-org.brum.beds.ac.uk/10.3390/v13071388 - 17 Jul 2021
Viewed by 595
Abstract
Currently there is no FDA-licensed vaccine or therapeutic against Sudan ebolavirus (SUDV) infections. The largest ever reported 2014–2016 West Africa outbreak, as well as the 2021 outbreak in the Democratic Republic of Congo, highlight the critical need for countermeasures against filovirus infections. A [...] Read more.
Currently there is no FDA-licensed vaccine or therapeutic against Sudan ebolavirus (SUDV) infections. The largest ever reported 2014–2016 West Africa outbreak, as well as the 2021 outbreak in the Democratic Republic of Congo, highlight the critical need for countermeasures against filovirus infections. A well-characterized small animal model that is susceptible to wild-type filoviruses would greatly add to the screening of antivirals and vaccines. Here, we infected signal transducer and activator of transcription-1 knock out (STAT-1 KO) mice with five different wildtype filoviruses to determine susceptibility. SUDV and Marburg virus (MARV) were the most virulent, and caused 100% or 80% lethality, respectively. Zaire ebolavirus (EBOV), Bundibugyo ebolavirus (BDBV), and Taï Forest ebolavirus (TAFV) caused 40%, 20%, and no mortality, respectively. Further characterization of SUDV in STAT-1 KO mice demonstrated lethality down to 3.1 × 101 pfu. Viral genomic material was detectable in serum as early as 1 to 2 days post-challenge. The onset of viremia was closely followed by significant changes in total white blood cells and proportion of neutrophils and lymphocytes, as well as by an influx of neutrophils in the liver and spleen. Concomitant significant fluctuations in blood glucose, albumin, globulin, and alanine aminotransferase were also noted, altogether consistent with other models of filovirus infection. Finally, favipiravir treatment fully protected STAT-1 KO mice from lethal SUDV challenge, suggesting that this may be an appropriate small animal model to screen anti-SUDV countermeasures. Full article
(This article belongs to the Special Issue In Vivo Mouse Models of Human Viral Infections)
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Article
Epstein–Barr Virus DNA Exacerbates Colitis Symptoms in a Mouse Model of Inflammatory Bowel Disease
Viruses 2021, 13(7), 1272; https://0-doi-org.brum.beds.ac.uk/10.3390/v13071272 - 29 Jun 2021
Viewed by 797
Abstract
Infection with EBV has been associated with various inflammatory disorders including inflammatory bowel diseases (IBD). Contribution of this virus to intestinal disease processes has not been assessed. We previously detected that EBV DNA triggers proinflammatory responses via the activation of endosomal Toll-like receptor [...] Read more.
Infection with EBV has been associated with various inflammatory disorders including inflammatory bowel diseases (IBD). Contribution of this virus to intestinal disease processes has not been assessed. We previously detected that EBV DNA triggers proinflammatory responses via the activation of endosomal Toll-like receptor (TLR) signaling. Hence, to examine the colitogenic potential of EBV DNA, we used the dextran sodium sulfate (DSS) mouse colitis model. C57BL/6J mice received either DSS-containing or regular drinking water. Mice were then administered EBV DNA by rectal gavage. Administration of EBV DNA to the DSS-fed mice aggravated colonic disease activity as well as increased the damage to the colon histologic architecture. Moreover, we observed enhanced expression of IL-17A, IFNγ and TNFα in colon tissues from the colitis mice (DSS-treated) given the EBV DNA compared to the other groups. This group also had a marked decrease in expression of the CTLA4 immunoregulatory marker. On the other hand, we observed enhanced expression of endosomal TLRs in colon tissues from the EBV DNA-treated colitis mice. These findings indicate that EBV DNA exacerbates proinflammatory responses in colitis. The ubiquity of EBV in the population indicates that possible similar responses may be of pertinence in a relevant proportion of IBD patients. Full article
(This article belongs to the Special Issue In Vivo Mouse Models of Human Viral Infections)
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