Microorganisms

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22 pages, 3062 KiB

Open AccessArticle

Extracellular Vesicles in Human Preterm Colostrum Inhibit Infection by Human Cytomegalovirus In Vitro

by Manuela Donalisio, Simona Cirrincione, Massimo Rittà, Cristina Lamberti, Andrea Civra, Rachele Francese, Paola Tonetto, Stefano Sottemano, Marcello Manfredi, Annalisa Lorenzato, Guido E. Moro, Marzia Giribaldi, Laura Cavallarin, Maria Gabriella Giuffrida, Enrico Bertino, Alessandra Coscia and David Lembo

Microorganisms 2020, 8(7), 1087; https://doi.org/10.3390/microorganisms8071087 - 21 Jul 2020

Cited by 18 | Viewed by 3370

Abstract

Breast milk is a complex biofluid that nourishes infants, supports their growth and protects them from diseases. However, at the same time, breastfeeding is a transmission route for human cytomegalovirus (HCMV), with preterm infants being at a great risk of congenital disease. The [...] Read more.

Breast milk is a complex biofluid that nourishes infants, supports their growth and protects them from diseases. However, at the same time, breastfeeding is a transmission route for human cytomegalovirus (HCMV), with preterm infants being at a great risk of congenital disease. The discrepancy between high HCMV transmission rates and the few reported cases of infants with severe clinical illness is likely due to the protective effect of breast milk. The aim of this study was to investigate the anti-HCMV activity of human preterm colostrum and clarify the role of colostrum-derived extracellular vesicles (EVs). Preterm colostrum samples were collected and the EVs were purified and characterized. The in vitro anti-HCMV activity of both colostrum and EVs was tested against HCMV, and the viral replication step inhibited by colostrum-purified EVs was examined. We investigated the putative role EV surface proteins play in impairing HCMV infection using shaving experiments and proteomic analysis. The obtained results confirmed the antiviral action of colostrum against HCMV and demonstrated a remarkable antiviral activity of colostrum-derived EVs. Furthermore, we demonstrated that EVs impair the attachment of HCMV to cells, with EV surface proteins playing a role in mediating this action. These findings contribute to clarifying the mechanisms that underlie the protective role of human colostrum against HCMV infection. Full article

(This article belongs to the Special Issue Cytomegalovirus: Biology and Infection)

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27 pages, 3899 KiB

Open AccessArticle

The Cytomegalovirus Tegument Protein UL35 Antagonizes Pattern Recognition Receptor-Mediated Type I IFN Transcription

by Markus Fabits, Vladimir Gonçalves Magalhães, Baca Chan, Virginie Girault, Endrit Elbasani, Elisa Rossetti, Eirikur Saeland, Martin Messerle, Andreas Pichlmair, Vanda Juranić Lisnić and Melanie M. Brinkmann

Microorganisms 2020, 8(6), 790; https://doi.org/10.3390/microorganisms8060790 - 26 May 2020

Cited by 21 | Viewed by 5263

Abstract

The rapid activation of pattern recognition receptor (PRR)-mediated type I interferon (IFN) signaling is crucial for the host response to infection. In turn, human cytomegalovirus (HCMV) must evade this potent response to establish life-long infection. Here, we reveal that the HCMV tegument protein [...] Read more.

The rapid activation of pattern recognition receptor (PRR)-mediated type I interferon (IFN) signaling is crucial for the host response to infection. In turn, human cytomegalovirus (HCMV) must evade this potent response to establish life-long infection. Here, we reveal that the HCMV tegument protein UL35 antagonizes the activation of type I IFN transcription downstream of the DNA and RNA sensors cGAS and RIG-I, respectively. We show that ectopic expression of UL35 diminishes the type I IFN response, while infection with a recombinant HCMV lacking UL35 induces an elevated type I IFN response compared to wildtype HCMV. With a series of luciferase reporter assays and the analysis of signaling kinetics upon HCMV infection, we observed that UL35 downmodulates PRR signaling at the level of the key signaling factor TANK-binding kinase 1 (TBK1). Finally, we demonstrate that UL35 and TBK1 co-immunoprecipitate when co-expressed in HEK293T cells. In addition, we show that a previously reported cellular binding partner of UL35, O-GlcNAc transferase (OGT), post-translationally GlcNAcylates UL35, but that this modification is not required for the antagonizing effect of UL35 on PRR signaling. In summary, we have identified UL35 as the first HCMV protein to antagonize the type I IFN response at the level of TBK1, thereby enriching our understanding of how this important herpesvirus escapes host immune responses. Full article

(This article belongs to the Special Issue Cytomegalovirus: Biology and Infection)

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8 pages, 216 KiB

Open AccessCommunication

Risk of Symptomatic Infection after Non-Primary Congenital Cytomegalovirus Infection

by Alessandra Coscia, Agata Leone, Carlotta Rubino, Ganna Galitska, Matteo Biolatti, Enrico Bertino, Chiara Peila and Francesco Cresi

Microorganisms 2020, 8(5), 786; https://doi.org/10.3390/microorganisms8050786 - 25 May 2020

Cited by 8 | Viewed by 3372

Abstract

Cytomegalovirus (CMV) is the leading cause of congenital infection. Its occurrence is phenotypically heterogeneous. The type of maternal infection, primary or non-primary, is an important factor related to the symptomatic disease, the primary infection was long considered the only cause of severe neonatal [...] Read more.

Cytomegalovirus (CMV) is the leading cause of congenital infection. Its occurrence is phenotypically heterogeneous. The type of maternal infection, primary or non-primary, is an important factor related to the symptomatic disease, the primary infection was long considered the only cause of severe neonatal disease. We aimed to analyze the association of primary and non-primary infection with pathological outcomes in infants and with long-term sequelae at follow-up. This was a monocentric retrospective observational study on a population of 91 infants diagnosed with a CMV infection at the Neonatal Care Unit of Neonatology at the Sant’Anna Hospital of Turin during the period of June 2005 to December 2018. Infants underwent clinical, laboratory, and neuroradiological evaluations at birth. Subsequently, the patients were monitored in an auxological, neurodevelopment, and audiological follow-up. Regarding primary vs. non-primary infection, we found a higher percentage of incidence of symptomatic and neurological localized infection, as well as long-term sequelae in the latter. However, no significant difference between the two populations was found. We underline the possibility of re-infection in previously immunized mothers (non-primary infection) with unfavorable neonatal and long-term outcomes. Full article

(This article belongs to the Special Issue Cytomegalovirus: Biology and Infection)

13 pages, 2253 KiB

Open AccessArticle

Pathophysiology of Hyperechogenic Bowel in Congenitally Human Cytomegalovirus Infected Fetuses

by Liliana Gabrielli, Maria P. Bonasoni, Angela Chiereghin, Giulia Piccirilli, Eva C. Borgatti, Giuliana Simonazzi, Nunzio C. M. Salfi, Ione Tamagnini and Tiziana Lazzarotto

Microorganisms 2020, 8(5), 779; https://doi.org/10.3390/microorganisms8050779 - 22 May 2020

Cited by 8 | Viewed by 3585

Abstract

Hyperechogenic bowel (HB) is a nonspecific ultrasound finding that can be associated with human cytomegalovirus (CMV) congenital infection. In this study, we investigated HB pathophysiology in CMV-infected fetuses. We examined small and large intestine as well as pancreas in 8 fetuses at 22 [...] Read more.

Hyperechogenic bowel (HB) is a nonspecific ultrasound finding that can be associated with human cytomegalovirus (CMV) congenital infection. In this study, we investigated HB pathophysiology in CMV-infected fetuses. We examined small and large intestine as well as pancreas in 8 fetuses at 22 weeks of gestation with congenital CMV infection. Ultrasound findings showed 4 fetuses with HB and 4 without. As negative group, 4 fetuses without CMV infection and without HB were studied. Immunohistochemistry for CMV, lymphocytic infiltrate, B-cell leukemia/lymphoma-2 (bcl-2), CD-117, cystic fibrosis transmembrane regulator (CFTR) were performed. HB fetuses showed multiple and sequential CMV-positive ganglion cells of Auerbach’s myenteric plexus. In the ganglia, bcl-2 was weakly expressed representing a reduced neuronal functionality. CD-117 revealed a regular distribution of Cajal cells, the pacemakers of intestinal contractility. Pancreas showed normal CFTR staining, indicating a preserved exocrine secretion, thus unlikely a contributory factor in HB. In CMV-infected fetuses without HB, CMV-positive cells were scatteredly found in ganglion cells and bcl-2 was strongly expressed. Intestinal CD-117 and pancreatic CFTR expression were similar to fetuses with HB. In conclusion, fetal CMV infection of the bowel may lead to peristalsis impairment (paralytic ileus) due to intestinal plexus involvement, which at ultrasound appeared as HB. Full article

(This article belongs to the Special Issue Cytomegalovirus: Biology and Infection)

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16 pages, 2684 KiB

Open AccessArticle

Strigolactone Analogs Are Promising Antiviral Agents for the Treatment of Human Cytomegalovirus Infection

by Matteo Biolatti, Marco Blangetti, Giulia D’Arrigo, Francesca Spyrakis, Paola Cappello, Camilla Albano, Paolo Ravanini, Santo Landolfo, Marco De Andrea, Cristina Prandi and Valentina Dell’Oste

Microorganisms 2020, 8(5), 703; https://doi.org/10.3390/microorganisms8050703 - 10 May 2020

Cited by 11 | Viewed by 3419

Abstract

The human cytomegalovirus (HCMV) is a widespread pathogen and is associated with severe diseases in immunocompromised individuals. Moreover, HCMV infection is the most frequent cause of congenital malformation in developed countries. Although nucleoside analogs have been successfully employed against HCMV, their use is [...] Read more.

The human cytomegalovirus (HCMV) is a widespread pathogen and is associated with severe diseases in immunocompromised individuals. Moreover, HCMV infection is the most frequent cause of congenital malformation in developed countries. Although nucleoside analogs have been successfully employed against HCMV, their use is hampered by the occurrence of serious side effects. There is thus an urgent clinical need for less toxic, but highly effective, antiviral drugs. Strigolactones (SLs) are a novel class of plant hormones with a multifaceted activity. While their role in plant-related fields has been extensively explored, their effects on human cells and their potential applications in medicine are far from being fully exploited. In particular, their antiviral activity has never been investigated. In the present study, a panel of SL analogs has been assessed for antiviral activity against HCMV. We demonstrate that TH-EGO and EDOT-EGO significantly inhibit HCMV replication in vitro, impairing late protein expression. Moreover, we show that the SL-dependent induction of apoptosis in HCMV-infected cells is a contributing mechanism to SL antiviral properties. Overall, our results indicate that SLs may be a promising alternative to nucleoside analogs for the treatment of HCMV infections. Full article

(This article belongs to the Special Issue Cytomegalovirus: Biology and Infection)

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18 pages, 2552 KiB

Open AccessArticle

Cytomegalovirus Strain TB40/E Restrictions and Adaptations to Growth in ARPE-19 Epithelial Cells

by Mai Vo, Alexis Aguiar, Michael A. McVoy and Laura Hertel

Microorganisms 2020, 8(4), 615; https://doi.org/10.3390/microorganisms8040615 - 24 Apr 2020

Cited by 17 | Viewed by 4126

Abstract

Despite displaying broad tropism in vivo, human cytomegalovirus (CMV) contained in bodily fluids replicates inefficiently in most cultured cell types except fibroblasts. As propagation in fibroblasts leads to the accumulation of genomic changes, a number of strains were generated by serial passaging on [...] Read more.

Despite displaying broad tropism in vivo, human cytomegalovirus (CMV) contained in bodily fluids replicates inefficiently in most cultured cell types except fibroblasts. As propagation in fibroblasts leads to the accumulation of genomic changes, a number of strains were generated by serial passaging on endothelial cells. One of these, TB40/E, was shown to contain a mixture of genetically distinct virus variants, and to retain tropism for fibroblasts, endothelial and epithelial cells. Cloning of an endotheliotropic subpopulation produced the TB40-BAC4 variant, extensively used in CMV tropism studies. Because TB40-BAC4 represents only one of the different variants comprising TB40/E, we generated a series of epithelial-cell adapted stocks derived from a TB40/E mixed stock, rather than from TB40-BAC4. Within two passages on ARPE-19 cells, virus populations were produced with the ability to enter and initiate replication with similar efficiencies in both epithelial cells and fibroblasts. Although the ability to release progeny also increased, cell-free virus yields from ARPE-19 cells remained consistently two to three-logs lower than from fibroblasts, hinting at the existence of a post-entry and post-genome synthesis block in epithelial cells. Multinucleated syncytia also rapidly appeared exclusively in ARPE-19 cell cultures, where their numbers and dimensions increased with virus passage. Irrespective of the number of infected nuclei comprising each syncytium, however, only one cytoplasmic virion assembly compartment was consistently observed, leading us to speculate that improvements in entry efficiency associated with ARPE-19 cell adaptation lead to the development of syncytia, which may negatively affect progeny release by limiting the amount of resources available to maturing virions. Full article

(This article belongs to the Special Issue Cytomegalovirus: Biology and Infection)

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11 pages, 3045 KiB

Open AccessArticle

Human Cytomegalovirus (HCMV) Reactivation in the Mammary Gland Induces a Proinflammatory Cytokine Shift in Breast Milk

by Tabea Rabe, Katrin Lazar, Christoffer Cambronero, Rangmar Goelz and Klaus Hamprecht

Microorganisms 2020, 8(2), 289; https://doi.org/10.3390/microorganisms8020289 - 20 Feb 2020

Cited by 21 | Viewed by 5213

Abstract

A locally restricted human cytomegalovirus (HCMV) reactivation in the mammary gland commonly occurs in nearly every IgG-seropositive breastfeeding mother. This unique phenomenon can therefore be used to study the reactivation process in an immunocompetent healthy host. Breast milk contains a variety of immunoactive [...] Read more.

A locally restricted human cytomegalovirus (HCMV) reactivation in the mammary gland commonly occurs in nearly every IgG-seropositive breastfeeding mother. This unique phenomenon can therefore be used to study the reactivation process in an immunocompetent healthy host. Breast milk contains a variety of immunoactive compounds, including immune cells, antibodies, growth factors, and cytokines supporting the newborn’s immature immune system. To characterize the impact of HCMV reactivation on breast milk cytokines, we analyzed longitudinal breast milk samples of four IgG-seropositive and three IgG-seronegative mothers of preterm infants using Proximity Extension Assay (PEA) technology (Olink Proteomics, Uppsala, Sweden). Cytokine profiling revealed elevated cytokine levels in IgG-seropositive mothers’ milk whey. Reactivating mothers showed higher levels of CC-chemokines (MCP-2, CCL19, and CCL20) and CXC-chemokines (IL-8, CXCL9, CXCL10, and CXCL11), such as the proinflammatory cytokine IL-17C, glycoprotein CD5, and TNFSF14. HCMV reactivation seems to influence the cytokine profile in human breast milk. This work could open the door for further studies analyzing distinct relations of the cytokine network as well as phenotypical and functional T cell properties in background of HCMV DNA dynamics in early lactation. Full article

(This article belongs to the Special Issue Cytomegalovirus: Biology and Infection)

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11 pages, 2773 KiB

Open AccessArticle

Adaptive and Innate Immune Cells in Fetal Human Cytomegalovirus-Infected Brains

by Yann Sellier, Florence Marliot, Bettina Bessières, Julien Stirnemann, Ferechte Encha-Razavi, Tiffany Guilleminot, Nacilla Haicheur, Franck Pages, Yves Ville and Marianne Leruez-Ville

Microorganisms 2020, 8(2), 176; https://doi.org/10.3390/microorganisms8020176 - 25 Jan 2020

Cited by 19 | Viewed by 2995

Abstract

Background: The understanding of the pathogenesis of cytomegalovirus (CMV)-induced fetal brain lesions is limited. We aimed to quantify adaptive and innate immune cells and CMV-infected cells in fetal brains with various degrees of brain damage. Methods: In total, 26 archived embedded fetal brains [...] Read more.

Background: The understanding of the pathogenesis of cytomegalovirus (CMV)-induced fetal brain lesions is limited. We aimed to quantify adaptive and innate immune cells and CMV-infected cells in fetal brains with various degrees of brain damage. Methods: In total, 26 archived embedded fetal brains were studied, of which 21 were CMV-infected and classified in severely affected (n = 13) and moderately affected (n = 8), and 5 were uninfected controls. The respective magnitude of infected cells, immune cells (CD8⁺, B cells, plasma cells, NK cells, and macrophages), and expression of immune checkpoint receptors (PD-1/PD-L1 and LAG-3) were measured by immunochemistry and quantified by quantitative imaging analysis. Results: Quantities of CD8⁺, plasma cells, NK cells, macrophages, and HCMV⁺ cells and expression of PD-1/PD-L1 and LAG-3 were significantly higher in severely affected than in moderately affected brains (all p values < 0.05). A strong link between higher number of stained cells for HCMV/CD8 and PD-1 and severity of brain lesions was found by component analysis. Conclusions: The higher expression of CD8, PD-1, and LAG-3 in severely affected brains could reflect immune exhaustion of cerebral T cells. These exhausted T cells could be ineffective in controlling viral multiplication itself, leading to more severe brain lesions. The study of the functionality of brain leucocytes ex vivo is needed to confirm this hypothesis. Full article

(This article belongs to the Special Issue Cytomegalovirus: Biology and Infection)

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11 pages, 2737 KiB

Open AccessArticle

NK Cells from RAG- or DCLRE1C-Deficient Patients Inhibit HCMV

by Zeguang Wu, Narmadha Subramanian, Eva-Maria Jacobsen, Kerstin Laib Sampaio, Johannes van der Merwe, Manfred Hönig and Thomas Mertens

Microorganisms 2019, 7(11), 546; https://doi.org/10.3390/microorganisms7110546 - 10 Nov 2019

Cited by 5 | Viewed by 2771

Abstract

The recombination-activating genes (RAGs) and the DNA cross-link repair 1C gene (DCLRE1C) encode the enzymes RAG1, RAG2 and Artemis. They are critical components of the V(D)J recombination machinery. V(D)J recombination is well known as a prerequisite for the development and antigen diversity of [...] Read more.

The recombination-activating genes (RAGs) and the DNA cross-link repair 1C gene (DCLRE1C) encode the enzymes RAG1, RAG2 and Artemis. They are critical components of the V(D)J recombination machinery. V(D)J recombination is well known as a prerequisite for the development and antigen diversity of T and B cells. New findings suggested that RAG deficiency impacts the cellular fitness and function of murine NK cells. It is not known whether NK cells from severe combined immunodeficiency (SCID) patients with defective RAGs or DCLRE1C (RAGs⁻/DCLRE1C⁻-NK) are active against virus infections. Here, we evaluated the anti-HCMV activity of RAGs⁻/DCLRE1C⁻-NK cells. NK cells from six SCID patients were functional in inhibiting HCMV transmission between cells in vitro. We also investigated the expansion of HCMV-induced NK cell subset in the RAG- or DCLRE1C-deficient patients. A dynamic expansion of NKG2C⁺ NK cells in one RAG-2-deficient patient was observed post HCMV acute infection. Our study firstly reveals the antiviral activity of human RAGs⁻/ DCLRE1C⁻-NK cells. Full article

(This article belongs to the Special Issue Cytomegalovirus: Biology and Infection)

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Review

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26 pages, 2311 KiB

Open AccessReview

Cytomegalovirus and Inflammatory Bowel Diseases (IBD) with a Special Focus on the Link with Ulcerative Colitis (UC)

by Alexandre Jentzer, Pauline Veyrard, Xavier Roblin, Pierre Saint-Sardos, Nicolas Rochereau, Stéphane Paul, Thomas Bourlet, Bruno Pozzetto and Sylvie Pillet

Microorganisms 2020, 8(7), 1078; https://doi.org/10.3390/microorganisms8071078 - 20 Jul 2020

Cited by 48 | Viewed by 15490

Abstract

Cytomegalovirus (CMV) infects approximately 40% of adults in France and persists lifelong as a latent agent in different organs, including gut. A close relationship is observed between inflammation that favors viral expression and viral replication that exacerbates inflammation. In this context, CMV colitis [...] Read more.

Cytomegalovirus (CMV) infects approximately 40% of adults in France and persists lifelong as a latent agent in different organs, including gut. A close relationship is observed between inflammation that favors viral expression and viral replication that exacerbates inflammation. In this context, CMV colitis may impact the prognosis of patients suffering from inflammatory bowel diseases (IBDs), and notably those with ulcerative colitis (UC). In UC, the mucosal inflammation and T helper cell (T_H) 2 cytokines, together with immunomodulatory drugs used for controlling flare-ups, favor viral reactivation within the gut, which, in turn, increases mucosal inflammation, impairs corticoid and immunosuppressor efficacy (the probability of steroid resistance is multiplied by more than 20 in the case of CMV colitis), and enhances the risk for colectomy. This review emphasizes the virological tools that are recommended for exploring CMV colitis during inflammatory bowel diseases (IBD) and underlines the interest of using ganciclovir for treating flare-ups associated to CMV colitis in UC patients. Full article

(This article belongs to the Special Issue Cytomegalovirus: Biology and Infection)

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22 pages, 3454 KiB

Open AccessReview

Mass Spectrometry-Based Characterization of the Virion Proteome, Phosphoproteome, and Associated Kinase Activity of Human Cytomegalovirus

by Yohann Couté, Alexandra Kraut, Christine Zimmermann, Nicole Büscher, Anne-Marie Hesse, Christophe Bruley, Marco De Andrea, Christina Wangen, Friedrich Hahn, Manfred Marschall and Bodo Plachter

Microorganisms 2020, 8(6), 820; https://doi.org/10.3390/microorganisms8060820 - 30 May 2020

Cited by 20 | Viewed by 4486

Abstract

The assembly of human cytomegalovirus (HCMV) virions is an orchestrated process that requires, as an essential prerequisite, the complex crosstalk between viral structural proteins. Currently, however, the mechanisms governing the successive steps in the constitution of virion protein complexes remain elusive. Protein phosphorylation [...] Read more.

The assembly of human cytomegalovirus (HCMV) virions is an orchestrated process that requires, as an essential prerequisite, the complex crosstalk between viral structural proteins. Currently, however, the mechanisms governing the successive steps in the constitution of virion protein complexes remain elusive. Protein phosphorylation is a key regulator determining the sequential changes in the conformation, binding, dynamics, and stability of proteins in the course of multiprotein assembly. In this review, we present a comprehensive map of the HCMV virion proteome, including a refined view on the virion phosphoproteome, based on previous publications supplemented by new results. Thus, a novel dataset of viral and cellular proteins contained in HCMV virions is generated, providing a basis for future analyses of individual phosphorylation steps and sites involved in the orchestrated assembly of HCMV virion-specific multiprotein complexes. Finally, we present the current knowledge on the activity of pUL97, the HCMV-encoded and virion-associated kinase, in phosphorylating viral and host proteins. Full article

(This article belongs to the Special Issue Cytomegalovirus: Biology and Infection)

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30 pages, 1581 KiB

Open AccessReview

Where do we Stand after Decades of Studying Human Cytomegalovirus?

by Francesca Gugliesi, Alessandra Coscia, Gloria Griffante, Ganna Galitska, Selina Pasquero, Camilla Albano and Matteo Biolatti

Microorganisms 2020, 8(5), 685; https://doi.org/10.3390/microorganisms8050685 - 8 May 2020

Cited by 62 | Viewed by 8735

Abstract

Human cytomegalovirus (HCMV), a linear double-stranded DNA betaherpesvirus belonging to the family of Herpesviridae, is characterized by widespread seroprevalence, ranging between 56% and 94%, strictly dependent on the socioeconomic background of the country being considered. Typically, HCMV causes asymptomatic infection in the immunocompetent [...] Read more.

Human cytomegalovirus (HCMV), a linear double-stranded DNA betaherpesvirus belonging to the family of Herpesviridae, is characterized by widespread seroprevalence, ranging between 56% and 94%, strictly dependent on the socioeconomic background of the country being considered. Typically, HCMV causes asymptomatic infection in the immunocompetent population, while in immunocompromised individuals or when transmitted vertically from the mother to the fetus it leads to systemic disease with severe complications and high mortality rate. Following primary infection, HCMV establishes a state of latency primarily in myeloid cells, from which it can be reactivated by various inflammatory stimuli. Several studies have shown that HCMV, despite being a DNA virus, is highly prone to genetic variability that strongly influences its replication and dissemination rates as well as cellular tropism. In this scenario, the few currently available drugs for the treatment of HCMV infections are characterized by high toxicity, poor oral bioavailability, and emerging resistance. Here, we review past and current literature that has greatly advanced our understanding of the biology and genetics of HCMV, stressing the urgent need for innovative and safe anti-HCMV therapies and effective vaccines to treat and prevent HCMV infections, particularly in vulnerable populations. Full article

(This article belongs to the Special Issue Cytomegalovirus: Biology and Infection)

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17 pages, 1023 KiB

Open AccessReview

Evolution and Genetic Diversity of Primate Cytomegaloviruses

by Rachele Cagliani, Diego Forni, Alessandra Mozzi and Manuela Sironi

Microorganisms 2020, 8(5), 624; https://doi.org/10.3390/microorganisms8050624 - 25 Apr 2020

Cited by 13 | Viewed by 4815

Abstract

Cytomegaloviruses (CMVs) infect many mammals, including humans and non–human primates (NHPs). Human cytomegalovirus (HCMV) is an important opportunistic pathogen among immunocompromised patients and represents the most common infectious cause of birth defects. HCMV possesses a large genome and very high genetic diversity. NHP–infecting [...] Read more.

Cytomegaloviruses (CMVs) infect many mammals, including humans and non–human primates (NHPs). Human cytomegalovirus (HCMV) is an important opportunistic pathogen among immunocompromised patients and represents the most common infectious cause of birth defects. HCMV possesses a large genome and very high genetic diversity. NHP–infecting CMVs share with HCMV a similar genomic organization and coding content, as well as the course of viral infection. Recent technological advances have allowed the sequencing of several HCMV strains from clinical samples and provided insight into the diversity of NHP–infecting CMVs. The emerging picture indicates that, with the exclusion of core genes (genes that have orthologs in all herpesviruses), CMV genomes are relatively plastic and diverse in terms of gene content, both at the inter– and at the intra–species level. Such variability most likely underlies the strict species–specificity of these viruses, as well as their ability to persist lifelong and with relatively little damage to their hosts. However, core genes, despite their strong conservation, also represented a target of adaptive evolution and subtle changes in their coding sequence contributed to CMV adaptation to different hosts. Indubitably, important knowledge gaps remain, the most relevant of which concerns the role of viral genetics in HCMV–associated human disease. Full article

(This article belongs to the Special Issue Cytomegalovirus: Biology and Infection)

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23 pages, 1318 KiB

Open AccessReview

The Cytomegalovirus Protein Kinase pUL97: Host Interactions, Regulatory Mechanisms and Antiviral Drug Targeting

by Mirjam Steingruber and Manfred Marschall

Microorganisms 2020, 8(4), 515; https://doi.org/10.3390/microorganisms8040515 - 4 Apr 2020

Cited by 39 | Viewed by 4966

Abstract

Human cytomegalovirus (HCMV) expresses a variety of viral regulatory proteins that undergo close interaction with host factors including viral-cellular multiprotein complexes. The HCMV protein kinase pUL97 represents a viral cyclin-dependent kinase ortholog (vCDK) that determines the efficiency of HCMV replication via phosphorylation of [...] Read more.

Human cytomegalovirus (HCMV) expresses a variety of viral regulatory proteins that undergo close interaction with host factors including viral-cellular multiprotein complexes. The HCMV protein kinase pUL97 represents a viral cyclin-dependent kinase ortholog (vCDK) that determines the efficiency of HCMV replication via phosphorylation of viral and cellular substrates. A hierarchy of functional importance of individual pUL97-mediated phosphorylation events has been discussed; however, the most pronounced pUL97-dependent phenotype could be assigned to viral nuclear egress, as illustrated by deletion of the UL97 gene or pharmacological pUL97 inhibition. Despite earlier data pointing to a cyclin-independent functionality, experimental evidence increasingly emphasized the role of pUL97-cyclin complexes. Consequently, the knowledge about pUL97 involvement in host interaction, viral nuclear egress and additional replicative steps led to the postulation of pUL97 as an antiviral target. Indeed, validation experiments in vitro and in vivo confirmed the sustainability of this approach. Consequently, current investigations of pUL97 in antiviral treatment go beyond the known pUL97-mediated ganciclovir prodrug activation and henceforward include pUL97-specific kinase inhibitors. Among a number of interesting small molecules analyzed in experimental and preclinical stages, maribavir is presently investigated in clinical studies and, in the near future, might represent a first kinase inhibitor applied in the field of antiviral therapy. Full article

(This article belongs to the Special Issue Cytomegalovirus: Biology and Infection)

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Other

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9 pages, 1784 KiB

Open AccessBrief Report

Human Cytomegalovirus Infection Suppresses CD34⁺ Progenitor Cell Engraftment in Humanized Mice

by Lindsey B. Crawford, Rebecca Tempel, Daniel N. Streblow, Andrew D. Yurochko, Felicia D. Goodrum, Jay A. Nelson and Patrizia Caposio

Microorganisms 2020, 8(4), 525; https://doi.org/10.3390/microorganisms8040525 - 6 Apr 2020

Cited by 8 | Viewed by 3237

Abstract

Human cytomegalovirus (HCMV) infection is a serious complication in hematopoietic stem cell transplant (HSCT) recipients due to virus-induced myelosuppression and impairment of stem cell engraftment. Despite the clear clinical link between myelosuppression and HCMV infection, little is known about the mechanism(s) by which [...] Read more.

Human cytomegalovirus (HCMV) infection is a serious complication in hematopoietic stem cell transplant (HSCT) recipients due to virus-induced myelosuppression and impairment of stem cell engraftment. Despite the clear clinical link between myelosuppression and HCMV infection, little is known about the mechanism(s) by which the virus inhibits normal hematopoiesis because of the strict species specificity and the lack of surrogate animal models. In this study, we developed a novel humanized mouse model system that recapitulates the HCMV-mediated engraftment failure after hematopoietic cell transplantation. We observed significant alterations in the hematopoietic populations in peripheral lymphoid tissues following engraftment of a subset of HCMV⁺ CD34⁺ hematopoietic progenitor cells (HPCs) within the transplant, suggesting that a small proportion of HCMV-infected CD34⁺ HPCs can profoundly affect HPC differentiation in the bone marrow microenvironment. This model will be instrumental to gain insight into the fundamental mechanisms of HCMV myelosuppression after HSCT and provides a platform to assess novel treatment strategies. Full article

(This article belongs to the Special Issue Cytomegalovirus: Biology and Infection)

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