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Understanding Human Cytomegalovirus Pathogenesis: Evidence from the Clinic and Laboratory...
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Understanding Human Cytomegalovirus Pathogenesis: Evidence from the Clinic and Laboratory Models

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

Deadline for manuscript submissions: 30 September 2024 | Viewed by 3763

Special Issue Editors

Dr. Mark R. Wills

E-Mail Website
Guest Editor
Department of Medicine and Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID), University of Cambridge, Cambridge CB2 1TN, UK
Interests: human cytomegalovirus (HCMV); anti-viral immune responses; latency and reactivation; host–pathogen interaction; cellular immunity
Dr. Sarah Jackson

E-Mail Website
Guest Editor
Department of Medicine and Cambridge Institute of Therapeutic Immunology and Infectious Disease (CITIID), University of Cambridge, Cambridge CB2 1TN, UK
Interests: human cytomegalovirus (HCMV); viral immunology; immune senescence; host–pathogen interaction; T-cells

Special Issue Information

Dear Colleagues,

Infection with human cytomegalovirus (HCMV) causes a significant health burden in multiple different clinical settings worldwide and, as such, the development of vaccines and novel treatment strategies for HCMV disease is deemed a very high priority. Generally, primary infection with HCMV is asymptomatic but still results in the establishment of a lifelong infection due to its ability, common to all herpes viruses, to establish a latent infection. Therefore, it is important to understand how to mitigate the impact of primary infection, reinfection, and reactivation of the latent virus in different clinical settings when developing new strategies and therapeutics for the control of HCMV in order to prevent its pathogenesis.  

The interaction of HCMV with the host is a dynamic process involving interactions at the individual cellular level (e.g., viral entry, establishment of latency, and reactivation) and at the systemic level where the immune response plays an essential role in determining the pathogenic outcome of infection and reactivation of the virus. This is evidenced by both the magnitude of immune evasion mechanisms encoded by HCMV and the outcomes seen in patients with diminished immune responses (e.g., in congenital infections or in immunosuppressed transplant patients). In this Pathogens Special Issue, we invite the submission of manuscripts that provide novel insights regarding our understanding of the elements of the immune response needed to control HCMV infection and reactivation and that address the molecular basis by which HCMV evades immune recognition to persist in the host. We welcome studies in the form of original research articles, reviews, or case reports from both human cell and clinical studies and pertinent animal models that inform our knowledge of the pathogenesis of HCMV.

Dr. Mark R. Wills
Dr. Sarah Jackson
Guest Editors

Manuscript Submission Information

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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

  • human cytomegalovirus (HCMV)
  • latency and reactivation
  • anti-viral immune responses
  • viral immune evasion
  • virus–host interaction and pathogenesis
  • congenital CMV
  • transplantation

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Published Papers (4 papers)

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Research

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17 pages, 5094 KiB  
Article
Establishment of a Luciferase-Based Reporter System to Study Aspects of Human Cytomegalovirus Infection, Replication Characteristics, and Antiviral Drug Efficacy
by Julia Tillmanns, Jintawee Kicuntod, Antonia Ehring, Endrit Elbasani, Eva Maria Borst, Debora Obergfäll, Regina Müller, Friedrich Hahn and Manfred Marschall
Pathogens 2024, 13(8), 645; https://doi.org/10.3390/pathogens13080645 - 31 Jul 2024
Viewed by 464
Abstract
Human cytomegalovirus (HCMV) represents a highly medically important pathogen which has constantly been the subject of both molecular and clinical investigations. HCMV infections, especially those in high-risk patients, still raise many unanswered questions, so current investigations are focused on viral pathogenesis, vaccine development, [...] Read more.
Human cytomegalovirus (HCMV) represents a highly medically important pathogen which has constantly been the subject of both molecular and clinical investigations. HCMV infections, especially those in high-risk patients, still raise many unanswered questions, so current investigations are focused on viral pathogenesis, vaccine development, and options for antiviral drug targeting. To this end, the use of suitable viral strains as well as recombinant reporter constructs in cultured cells and model systems has specific significance. We previously reported on the application of various herpesviruses that express green, red, or related fluorescent proteins, especially in the fields of virus–host interaction and antiviral research. Here, we characterized a recombinant version of the clinically relevant and cell type-adaptable HCMV strain TB40, which expresses firefly luciferase as a quantitative reporter of viral replication (TB40-FLuc). The data provide evidence for five main conclusions. First, HCMV TB40-FLuc is employable in multiple settings in primary human cells. Second, viral reporter signals are easily quantifiable, even at early time points within viral replication. Third, the FLuc reporter reflects the kinetics of viral intracellular replication, cascade-like viral IE-E-L protein production, and progeny release. Fourth, as relates to specific applications of the TB40-FLuc system, we demonstrated the reliability of quantitative antiviral compound determination in multi-well formats and its independence from fluorescence-based measurements in the case of autofluorescent inhibitors. Finally, we illustrated increased reporter sensitivity in comparison to other recombinant HCMVs. In essence, recombinant HCMV TB40-FLuc combines several molecular properties that are considered beneficial in studies on viral host tropism, replication efficiency, and antiviral drug assessment. Full article
(This article belongs to the Special Issue Understanding Human Cytomegalovirus Pathogenesis: Evidence from the Clinic and Laboratory Models)
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12 pages, 1728 KiB  
Article
The Triterpenoid MOMORDIN-Ic Inhibits HCMV by Preventing the Initiation of Gene Expression in Eukaryotic Cells
by Eleanor Bradley, Emma Poole and Matthew B. Reeves
Pathogens 2024, 13(7), 546; https://doi.org/10.3390/pathogens13070546 - 28 Jun 2024
Viewed by 484
Abstract
Human cytomegalovirus (HCMV) primary infection, re-infection, and reactivation from latency cause morbidity in immune-compromised patients. Consequently, potential therapeutic strategies remain of interest for the treatment of infection. Naturally occurring triterpenoids derived from plants have been demonstrated to have anti-viral activity, although their precise [...] Read more.
Human cytomegalovirus (HCMV) primary infection, re-infection, and reactivation from latency cause morbidity in immune-compromised patients. Consequently, potential therapeutic strategies remain of interest for the treatment of infection. Naturally occurring triterpenoids derived from plants have been demonstrated to have anti-viral activity, although their precise mechanisms of action are not always fully understood. Here, we investigate the activity of Mormordin Ic (Mc) and demonstrate that it is potently anti-viral against HCMV. Through investigation of the mechanistic basis of this anti-viral activity, we identify that it is inhibitory to both viral and host gene expression, and to highly induced genes in particular. We go on to observe that Mc impacts on RNA Pol II activity and, specifically, reduces the occupancy of elongating RNA Pol II at a viral promoter. Next, we demonstrate that Mc is inhibitory to HCMV reactivation, and in doing so identify that it has greater activity against the canonical major immediate early promoter compared to the alternative ip2 promoter located downstream. Finally, we see evidence of RNA Pol II occupancy at the ip2 promoter in undifferentiated myeloid cells. Thus, Mc is potently anti-viral and a potential tool to probe the activity of multiple promoters considered important for controlling HCMV reactivation. Full article
(This article belongs to the Special Issue Understanding Human Cytomegalovirus Pathogenesis: Evidence from the Clinic and Laboratory Models)
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Review

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22 pages, 632 KiB  
Review
The Wide Spectrum of Presentations of Cytomegalovirus Infection in Immunocompetent Hosts: An Exhaustive Narrative Review
by Ami Schattner
Pathogens 2024, 13(8), 667; https://doi.org/10.3390/pathogens13080667 - 7 Aug 2024
Viewed by 519
Abstract
CMV is a ubiquitous DNA virus that establishes infection and results in 40–100% seropositivity. Viral replication occurs following an acquired primary infection (or reinfection) or by the reactivation of life-long latency. In immunocompetent patients, CMV infection is mostly asymptomatic or mild and self-limited. [...] Read more.
CMV is a ubiquitous DNA virus that establishes infection and results in 40–100% seropositivity. Viral replication occurs following an acquired primary infection (or reinfection) or by the reactivation of life-long latency. In immunocompetent patients, CMV infection is mostly asymptomatic or mild and self-limited. However, an extensive review of the literature published up to April 2024 reveals that despite immunocompetence, CMV can cause a very large variety of clinical syndromes in any part of the gastrointestinal tract (the most common pattern), the central or peripheral nervous system, and the eyes, as well as hematological, pulmonary, cardiac, and cutaneous disease. Not uncommonly, more than one system is involved, and though the disease is often self-limited, treatment with intravenous ganciclovir or oral valganciclovir may be required, and in isolated cases, fatalities may occur. Thus, a potential CMV infection should be considered in the differential of myriad syndromes in non-immunocompromised patients. Associated systemic symptoms (fever, sweats, and weight loss), lymphocytosis, and hepatitis are not uncommon and can be a useful clue. Some populations, such as critically ill patients in intensive care, pregnant women, elderly patients, and those with inflammatory bowel disease, may be more susceptible. Moreover, the potential of past, latent CMV infection (i.e., CMV seropositivity) to be associated with significant cardiovascular morbidity and all-cause mortality years later is intriguing and requires further study. All these data indicate the outstanding importance of developing a vaccine against CMV, which hopefully will become available in the foreseeable future. Meanwhile, a solid diagnosis of active CMV infection can be quickly established (or ruled out) by widely available serology tests and PCR amplification, and clinicians in all disciplines need to be more aware of the diverse guises of CMV infection and remember to consider it in any host, including an immunocompetent one. Full article
(This article belongs to the Special Issue Understanding Human Cytomegalovirus Pathogenesis: Evidence from the Clinic and Laboratory Models)
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13 pages, 261 KiB  
Review
Human Cytomegalovirus Infection and Neurocognitive and Neuropsychiatric Health
by Shawn D. Gale, Thomas J. Farrer, Reagan Erbstoesser, Scott MacLean and Dawson W. Hedges
Pathogens 2024, 13(5), 417; https://doi.org/10.3390/pathogens13050417 - 16 May 2024
Viewed by 1532
Abstract
A common infection, human cytomegalovirus (HCMV) has been associated with a variety of human diseases, including cardiovascular disease and possibly certain cancers. HCMV has also been associated with cognitive, psychiatric, and neurological conditions. Children with congenital or early-life HCMV are at risk for [...] Read more.
A common infection, human cytomegalovirus (HCMV) has been associated with a variety of human diseases, including cardiovascular disease and possibly certain cancers. HCMV has also been associated with cognitive, psychiatric, and neurological conditions. Children with congenital or early-life HCMV are at risk for microcephaly, cerebral palsy, and sensorineural hearing loss, although in many cases sensorineural loss may resolve. In addition, HCMV can be associated with neurodevelopmental impairment, which may improve with time. In young, middle-aged, and older adults, HCMV has been adversely associated with cognitive function in some but not in all studies. Research has linked HCMV to Alzheimer’s and vascular dementia, but again not all findings consistently support these associations. In addition, HCMV has been associated with depressive disorder, bipolar disorder, anxiety, and autism-spectrum disorder, although the available findings are likewise inconsistent. Given associations between HCMV and a variety of neurocognitive and neuropsychiatric disorders, additional research investigating reasons for the considerable inconsistencies in the currently available findings is needed. Additional meta-analyses and more longitudinal studies are needed as well. Research into the effects of antiviral medication on cognitive and neurological outcomes and continued efforts in vaccine development have potential to lower the neurocognitive, neuropsychiatric, and neurological burden of HCMV infection. Full article
(This article belongs to the Special Issue Understanding Human Cytomegalovirus Pathogenesis: Evidence from the Clinic and Laboratory Models)
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