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Pathogens
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Murine Models of Cytomegalovirus Infection
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Murine Models of Cytomegalovirus Infection

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

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 27725

Special Issue Editors

Dr. Niels A. Lemmermann

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Guest Editor
Institute for Virology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany
Interests: murine models of CMV infection after hematopoietic cell transplantation; murine models of CMV latency and reactivation; CMV immune control and immune evasion; role of mast cells during CMV infection
Dr. Vanda Juranic Lisnic

E-Mail Website
Guest Editor
Department of Histology and Embryology and Center for Proteomics, University of Rijeka, Faculty of Medicine, Croatia
Interests: pathogenesis of CMV in reproductive organs and impact on fertility; CMV virus biology; CMV immune control and immune evasion; CMV and NK cells; CMV and missing-self evasion

Special Issue Information

Dear Colleagues,

The human cytomegalovirus (HCMV) is the prototypic member of the beta-herpesviruses and infects the majority of people worldwide. The immune system of the immunocompetent host controls the infection with high efficiency, but latent viral genomes are maintained lifelong in body cells. A clinical challenge is the reactivation of HCMV under conditions of immunosuppression in case of hematopoietic cell transplantation or after solid organ transplantation. Another outstanding and highly relevant issue is the primary HCMV infection of the fetus during pregnancy that can result in multi-organ disease and is the leading cause of virus-induced birth defects. Furthermore, latent HCMV infection has been proposed as a co-morbidity factor in chronic inflammatory diseases (e.g. arteriosclerosis) and malignant tumors.

Million years of co-evolution of cytomegaloviruses and their respective host lead to species-specific replication of the virus and to host adaptation that prevents the investigation of HCMV infection in animal models including non-human primates. To circumvent this limitation, animal models of the specific virus-host pair have been developed in the last decades allowing to study basic principles of viral pathogenesis and to address urgent clinical questions that are difficult to study in humans. The currently most versatile model is the murine infection with mouse cytomegalovirus (mCMV). This model emulates many aspects of the infection, including virus-host interactions, viral pathogenesis, and the development of therapeutic options.

For this Pathogens Special Issue, we invite submissions in the form of original research articles and reviews that give new insight into this well-defined model of an important but neglected human pathogen. All research focusing on relevant aspects of the infection are welcome, in particular preclinical models of CMV diseases and antiviral treatment, viral latency and reactivation, as well as investigations of virus-host interactions. We look forward to receiving your contributions.

Dr. Niels A. Lemmermann
Dr. Vanda Juranic Lisnic
Guest Editors

Manuscript Submission Information

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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 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

  • antiviral immune response
  • co-morbidity
  • congenital CMV infection
  • hematopoietic cell transplantation
  • immunotherapy
  • latency and reactivation
  • memory formation and memory inflation
  • organ manifestation
  • solid organ transplantation
  • vaccines
  • viral pathogenesis
  • virus-host interaction

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Published Papers (9 papers)

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Research

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17 pages, 3411 KiB  
Article
MCMV Centrifugal Enhancement: A New Spin on an Old Topic
by Trevor J. Hancock, Morgan Lynn Hetzel, Andrea Ramirez and Tim E. Sparer
Pathogens 2021, 10(12), 1577; https://doi.org/10.3390/pathogens10121577 - 3 Dec 2021
Viewed by 2765
Abstract
Human cytomegalovirus (HCMV) is a ubiquitous pathogen infecting a majority of people worldwide, with diseases ranging from mild to life-threatening. Its clinical relevance in immunocompromised people and congenital infections have made treatment and vaccine development a top priority. Because of cytomegaloviruses’ species specificity, [...] Read more.
Human cytomegalovirus (HCMV) is a ubiquitous pathogen infecting a majority of people worldwide, with diseases ranging from mild to life-threatening. Its clinical relevance in immunocompromised people and congenital infections have made treatment and vaccine development a top priority. Because of cytomegaloviruses’ species specificity, murine cytomegalovirus (MCMV) models have historically informed and advanced translational CMV therapies. Using the phenomenon of centrifugal enhancement, we explored differences between MCMVs derived in vitro and in vivo. We found centrifugal enhancement on tissue culture-derived virus (TCV) was ~3× greater compared with salivary gland derived virus (SGV). Using novel “flow virometry”, we found that TCV contained a distinct submicron particle composition compared to SGV. Using an inhibitor of exosome production, we show these submicron particles are not extracellular vesicles that contribute to centrifugal enhancement. We examined how these differences in submicron particles potentially contribute to differing centrifugal enhancement phenotypes, as well as broader in vivo vs. in vitro MCMV differences. Full article
(This article belongs to the Special Issue Murine Models of Cytomegalovirus Infection)
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18 pages, 1481 KiB  
Article
Immunodominant Cytomegalovirus Epitopes Suppress Subdominant Epitopes in the Generation of High-Avidity CD8 T Cells
by Kirsten Freitag, Sara Hamdan, Matthias J. Reddehase and Rafaela Holtappels
Pathogens 2021, 10(8), 956; https://doi.org/10.3390/pathogens10080956 - 29 Jul 2021
Cited by 6 | Viewed by 2443
Abstract
CD8+ T-cell responses to pathogens are directed against infected cells that present pathogen-encoded peptides on MHC class-I molecules. Although natural responses are polyclonal, the spectrum of peptides that qualify for epitopes is remarkably small even for pathogens with high coding capacity. Among [...] Read more.
CD8+ T-cell responses to pathogens are directed against infected cells that present pathogen-encoded peptides on MHC class-I molecules. Although natural responses are polyclonal, the spectrum of peptides that qualify for epitopes is remarkably small even for pathogens with high coding capacity. Among those few that are successful at all, a hierarchy exists in the magnitude of the response that they elicit in terms of numbers of CD8+ T cells generated. This led to a classification into immunodominant and non-immunodominant or subordinate epitopes, IDEs and non-IDEs, respectively. IDEs are favored in the design of vaccines and are chosen for CD8+ T-cell immunotherapy. Using murine cytomegalovirus as a model, we provide evidence to conclude that epitope hierarchy reflects competition on the level of antigen recognition. Notably, high-avidity cells specific for non-IDEs were found to expand only when IDEs were deleted. This may be a host’s back-up strategy to avoid viral immune escape through antigenic drift caused by IDE mutations. Importantly, our results are relevant for the design of vaccines based on cytomegaloviruses as vectors to generate high-avidity CD8+ T-cell memory specific for unrelated pathogens or tumors. We propose the deletion of vector-encoded IDEs to avoid the suppression of epitopes of the vaccine target. Full article
(This article belongs to the Special Issue Murine Models of Cytomegalovirus Infection)
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21 pages, 16046 KiB  
Article
The m15 Locus of Murine Cytomegalovirus Modulates Natural Killer Cell Responses to Promote Dissemination to the Salivary Glands and Viral Shedding
by Baca Chan, Maja Arapović, Laura L. Masters, Francois Rwandamuiye, Stipan Jonjić, Lee M. Smith and Alec J. Redwood
Pathogens 2021, 10(7), 866; https://doi.org/10.3390/pathogens10070866 - 9 Jul 2021
Cited by 2 | Viewed by 2545
Abstract
As the largest herpesviruses, the 230 kb genomes of cytomegaloviruses (CMVs) have increased our understanding of host immunity and viral escape mechanisms, although many of the annotated genes remain as yet uncharacterised. Here we identify the m15 locus of murine CMV (MCMV) as [...] Read more.
As the largest herpesviruses, the 230 kb genomes of cytomegaloviruses (CMVs) have increased our understanding of host immunity and viral escape mechanisms, although many of the annotated genes remain as yet uncharacterised. Here we identify the m15 locus of murine CMV (MCMV) as a viral modulator of natural killer (NK) cell immunity. We show that, rather than discrete transcripts from the m14, m15 and m16 genes as annotated, there are five 3′-coterminal transcripts expressed over this region, all utilising a consensus polyA tail at the end of the m16 gene. Functional inactivation of any one of these genes had no measurable impact on viral replication. However, disruption of all five transcripts led to significantly attenuated dissemination to, and replication in, the salivary glands of multiple strains of mice, but normal growth during acute infection. Disruption of the m15 locus was associated with heightened NK cell responses, including enhanced proliferation and IFNγ production. Depletion of NK cells, but not T cells, rescued salivary gland replication and viral shedding. These data demonstrate the identification of multiple transcripts expressed by a single locus which modulate, perhaps in a concerted fashion, the function of anti-viral NK cells. Full article
(This article belongs to the Special Issue Murine Models of Cytomegalovirus Infection)
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Review

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13 pages, 1416 KiB  
Review
CD4 T Cell-Mediated Immune Control of Cytomegalovirus Infection in Murine Salivary Glands
by Nathan Zangger, Josua Oderbolz and Annette Oxenius
Pathogens 2021, 10(12), 1531; https://doi.org/10.3390/pathogens10121531 - 23 Nov 2021
Cited by 8 | Viewed by 3058
Abstract
CD4 T cells are well known for their supportive role in CD8 T cell and B cell responses during viral infection. However, during murine cytomegalovirus (MCMV) infection in the salivary glands (SGs), CD4 T cells exhibit direct antiviral effector functions to control the [...] Read more.
CD4 T cells are well known for their supportive role in CD8 T cell and B cell responses during viral infection. However, during murine cytomegalovirus (MCMV) infection in the salivary glands (SGs), CD4 T cells exhibit direct antiviral effector functions to control the infection. In this mucosal organ, opposed to other infected tissues, MCMV establishes a sustained lytic replication that lasts for several weeks. While the protective function of CD4 T cells is exerted through the production of the pro-inflammatory cytokines interferon gamma (IFNγ) and tumor necrosis factor alpha (TNF), the reasons for their markedly delayed control of lytic MCMV infection remain elusive. Here, we review the current knowledge on the dynamics and mechanisms of the CD4 T cell-mediated control of MCMV-infected SGs, including their localization in the SG in relation to MCMV infected cells and other immune cells, their mode of action, and their regulation. Full article
(This article belongs to the Special Issue Murine Models of Cytomegalovirus Infection)
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23 pages, 10218 KiB  
Review
Murine Models of Central Nervous System Disease following Congenital Human Cytomegalovirus Infections
by Jerome Moulden, Cathy Yea Won Sung, Ilija Brizic, Stipan Jonjic and William Britt
Pathogens 2021, 10(8), 1062; https://doi.org/10.3390/pathogens10081062 - 21 Aug 2021
Cited by 15 | Viewed by 3105
Abstract
Human cytomegalovirus infection of the developing fetus is a leading cause of neurodevelopmental disorders in infants and children, leading to long-term neurological sequela in a significant number of infected children. Current understanding of the neuropathogenesis of this intrauterine infection is limited because of [...] Read more.
Human cytomegalovirus infection of the developing fetus is a leading cause of neurodevelopmental disorders in infants and children, leading to long-term neurological sequela in a significant number of infected children. Current understanding of the neuropathogenesis of this intrauterine infection is limited because of the complexity of this infection, which includes maternal immunological responses that are overlaid on virus replication in the CNS during neurodevelopment. Furthermore, available data from human cases are observational, and tissues from autopsy studies have been derived from only the most severe infections. Animal models of this human infection are also limited by the strict species specificity of cytomegaloviruses. However, informative models including non-human primates and small animal models have been developed. These include several different murine models of congenital HCMV infection for the study of CMV neuropathogenesis. Although individual murine models do not completely recapitulate all aspects of the human infection, each model has provided significant information that has extended current understanding of the neuropathogenesis of this human infection. This review will compare and contrast different murine models in the context of available information from human studies of CNS disease following congenital HCMV infections. Full article
(This article belongs to the Special Issue Murine Models of Cytomegalovirus Infection)
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14 pages, 494 KiB  
Review
Licensing Natural Killers for Antiviral Immunity
by John M. Cronk, Eleni Fafoutis and Michael G. Brown
Pathogens 2021, 10(7), 908; https://doi.org/10.3390/pathogens10070908 - 19 Jul 2021
Cited by 5 | Viewed by 4410
Abstract
Immunoreceptor tyrosine-based inhibitory motif (ITIM)-bearing receptors (IRs) enable discrimination between self- and non-self molecules on the surface of host target cells. In this regard, they have a vital role in self-tolerance through binding and activating intracellular tyrosine phosphatases which can inhibit cellular activation. [...] Read more.
Immunoreceptor tyrosine-based inhibitory motif (ITIM)-bearing receptors (IRs) enable discrimination between self- and non-self molecules on the surface of host target cells. In this regard, they have a vital role in self-tolerance through binding and activating intracellular tyrosine phosphatases which can inhibit cellular activation. Yet, self-MHC class I (MHC I)-specific IRs are versatile in that they can also positively impact lymphocyte functionality, as exemplified by their role in natural killer (NK) cell education, often referred to as ’licensing‘. Recent discoveries using defined mouse models of cytomegalovirus (CMV) infection have revealed that select self-MHC I IRs can increase NK cell antiviral defenses as well, whereas other licensing IRs cannot, or instead impede virus-specific NK responses for reasons that remain poorly understood. This review highlights a role for self-MHC I ‘licensing’ IRs in antiviral immunity, especially in the context of CMV infection, their impact on virus-specific NK cells during acute infection, and their potential to affect viral pathogenesis and disease. Full article
(This article belongs to the Special Issue Murine Models of Cytomegalovirus Infection)
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15 pages, 298 KiB  
Review
A Mouse Model That Mimics AIDS-Related Cytomegalovirus Retinitis: Insights into Pathogenesis
by Jay J. Oh, Jessica J. Carter and Richard D. Dix
Pathogens 2021, 10(7), 850; https://doi.org/10.3390/pathogens10070850 - 6 Jul 2021
Cited by 3 | Viewed by 2420
Abstract
With the appearance of the worldwide AIDS pandemic four decades ago came a number of debilitating opportunistic infections in patients immunosuppressed by the pathogenic human retrovirus HIV. Among these was a severe sight-threatening retinal disease caused by human cytomegalovirus (HCMV) that remains today [...] Read more.
With the appearance of the worldwide AIDS pandemic four decades ago came a number of debilitating opportunistic infections in patients immunosuppressed by the pathogenic human retrovirus HIV. Among these was a severe sight-threatening retinal disease caused by human cytomegalovirus (HCMV) that remains today a significant cause of vision loss and blindness in untreated AIDS patients without access or sufficient response to combination antiretroviral therapy. Early investigations of AIDS-related HCMV retinitis quickly characterized its hallmark clinical features and unique histopathologic presentation but did not begin to identify the precise virologic and immunologic events that allow the onset and development of this retinal disease during HIV-induced immunosuppression. Toward this end, several mouse models of experimental cytomegalovirus retinitis have been developed to provide new insights into the pathophysiology of HCMV retinitis during AIDS. Herein, we provide a summary and comparison of these mouse models of AIDS-related HCMV retinitis with particular emphasis on one mouse model developed in our laboratory in which mice with a murine acquired immunodeficiency syndrome (MAIDS) of murine retrovirus origin develops a reproducible and well characterized retinitis following intraocular infection with murine cytomegalovirus (MCMV). The MAIDS model of MCMV retinitis has advanced the discovery of many clinically relevant virologic and immunologic mechanisms of virus-induced retinal tissue destruction that are discussed and summarized in this review. These findings may extend to the pathogenesis of AIDS-related HCMV retinitis and other AIDS-related opportunistic virus infections. Full article
(This article belongs to the Special Issue Murine Models of Cytomegalovirus Infection)
11 pages, 592 KiB  
Review
Don’t Go Breaking My Heart: MCMV as a Model for HCMV-Associated Cardiovascular Diseases
by Cassandra M. Bonavita and Rhonda D. Cardin
Pathogens 2021, 10(5), 619; https://doi.org/10.3390/pathogens10050619 - 18 May 2021
Cited by 11 | Viewed by 2724
Abstract
Human Cytomegalovirus (HCMV) is a widespread pathogen that causes lifelong latent infection and is associated with the exacerbation of chronic inflammatory diseases in seropositive individuals. Of particular impact, HCMV infection is known to worsen many cardiovascular diseases including myocarditis, atherosclerosis, hypertension, and transplant [...] Read more.
Human Cytomegalovirus (HCMV) is a widespread pathogen that causes lifelong latent infection and is associated with the exacerbation of chronic inflammatory diseases in seropositive individuals. Of particular impact, HCMV infection is known to worsen many cardiovascular diseases including myocarditis, atherosclerosis, hypertension, and transplant vasculopathy. Due to its similarity to HCMV, murine CMV (MCMV) is an appropriate model to understand HCMV-induced pathogenesis in the heart and vasculature. MCMV shares similar sequence homology and recapitulates much of the HCMV pathogenesis, including HCMV-induced cardiovascular diseases. This review provides insight into HCMV-associated cardiovascular diseases and the murine model of MCMV infection, which has been used to study the viral pathogenesis and mechanisms contributing to cardiovascular diseases. Our new functional studies using echocardiography demonstrate tachycardia and hypertrophy in the mouse, similar to HCMV-induced myocarditis in humans. For the first time, we show long term heart dysfunction and that MCMV reactivates from latency in the heart, which raises the intriguing idea that HCMV latency and frequent virus reactivation perturbs long term cardiovascular function. Full article
(This article belongs to the Special Issue Murine Models of Cytomegalovirus Infection)
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Other

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10 pages, 1028 KiB  
Brief Report
Direct Evidence for Viral Antigen Presentation during Latent Cytomegalovirus Infection
by Niels A. W. Lemmermann and Matthias J. Reddehase
Pathogens 2021, 10(6), 731; https://doi.org/10.3390/pathogens10060731 - 10 Jun 2021
Cited by 5 | Viewed by 2813
Abstract
Murine models of cytomegalovirus (CMV) infection have revealed an immunological phenomenon known as “memory inflation” (MI). After a peak of a primary CD8+ T-cell response, the pool of epitope-specific cells contracts in parallel to the resolution of productive infection and the establishment [...] Read more.
Murine models of cytomegalovirus (CMV) infection have revealed an immunological phenomenon known as “memory inflation” (MI). After a peak of a primary CD8+ T-cell response, the pool of epitope-specific cells contracts in parallel to the resolution of productive infection and the establishment of a latent infection, referred to as “latency.” CMV latency is associated with an increase in the number of cells specific for certain viral epitopes over time. The inflationary subset was identified as effector-memory T cells (iTEM) characterized by the cell surface phenotype KLRG1+CD127−CD62L−. As we have shown recently, latent viral genomes are not transcriptionally silent. Rather, viral genes are sporadically desilenced in a stochastic fashion. The current hypothesis proposes MI to be driven by presented viral antigenic peptides encoded by the corresponding, stochastically expressed viral genes. Although this mechanism suggests itself, independent evidence for antigen presentation during viral latency is pending. Here we fill this gap by showing that T cell-receptor transgenic OT-I cells that are specific for peptide SIINFEKL proliferate upon adoptive cell transfer in C57BL/6 recipients latently infected with murine CMV encoding SIINFEKL (mCMV-SIINFEKL), but not in those latently infected with mCMV-SIINFEKA, in which antigenicity is lost by mutation L8A of the C-terminal amino acid residue. Full article
(This article belongs to the Special Issue Murine Models of Cytomegalovirus Infection)
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