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17 pages, 3411 KiB

Open AccessArticle

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 2344

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

Open AccessArticle

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 2049

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

Open AccessArticle

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 1 | Viewed by 2217

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

Open AccessReview

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 4 | Viewed by 2533

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

Open AccessReview

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 12 | Viewed by 2688

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

Open AccessReview

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 3813

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

Open AccessReview

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 2 | Viewed by 2070

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

Open AccessReview

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 9 | Viewed by 2253

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

Open AccessBrief 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 2444

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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