Biology of Cytomegalovirus Infection

A special issue of Life (ISSN 2075-1729). This special issue belongs to the section "Cell Biology and Tissue Engineering".

Deadline for manuscript submissions: closed (5 July 2021)

Special Issue Editors


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Guest Editor
Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia
Interests: endocytosis; antigen presentation; cytomegalovirus biology; protein trafficking
Special Issues, Collections and Topics in MDPI journals

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Guest Editor
Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia
Interests: cell biology; virology; endocytic trafficking; endosomal recycling

E-Mail Website
Guest Editor
Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia
Interests: cellular physiology; endocytosis

Special Issue Information

Dear Colleagues,

Herpesviruses extensively reorganize membranous organelles of cells to establish a proper environment for the assembly of virions and virus shedding. Beta-herpesviruses, for example, establish a new organelle structure, which is the size of the nucleus. Most of these alterations are associated with the development of the cytoplasmic virus-manufacturing factory, known as the assembly compartment (AC). The composition and the biogenesis of AC are far from being understood. These extensive reorganizations are associated with reshaping of the cytoskeleton, alteration of the cytokinesis machinery, reconfiguration of membranous domains and compartments, redirection of the membrane flow in the infected cell, reshaping the autophagy, etc. The extensive reorganizations are associated with the alteration of many cellular processes, such as endosomal recycling and redistribution of cellular proteins, with many systemic physiological consequences, such as immune evasion. All these alterations are associated either with the expression of herpesvirus genes and their interaction with the cellular regulatory machinery or cellular stress associated with the infection.

This Special Issue will discuss the biogenesis of the AC, reshaping the cellular physiology of the membranous system during herpesvirus infection, reorganization of the host-cell machinery, and regulatory cascades that shape the membranous system of the cells and virus tools used for such extensive alterations of the host cell. Discussion of what we can learn from herpesviruses as cell biologists is of particular interest. Namely, it is clear that the shaping of the membranous system is quite complex and involves at least four thousand host-cell factors (genes) that are aligned into a functional network, which is far from being fully understood. Thus, an understanding of herpesvirus-induced alterations may significantly contribute to the understanding of the physiology of membranous systems.

Prof. Dr. Pero Lučin
Dr. Hana Mahmutefendić Lučin
Dr. Gordana Blagojević Zagorac
Guest Editors

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Keywords

  • Herpesvirus infection
  • Assembly compartment
  • Herpesvirus egress
  • Membranous system
  • Endosomes
  • The Golgi
  • Cytokinesis

Published Papers (5 papers)

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Research

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13 pages, 1522 KiB  
Article
Localization of Viral Epitope-Specific CD8 T Cells during Cytomegalovirus Latency in the Lungs and Recruitment to Lung Parenchyma by Airway Challenge Infection
by Franziska Blaum, Dominika Lukas, Matthias J. Reddehase and Niels A. W. Lemmermann
Life 2021, 11(9), 918; https://doi.org/10.3390/life11090918 - 4 Sep 2021
Cited by 3 | Viewed by 1789
Abstract
Interstitial pneumonia is a life-threatening clinical manifestation of cytomegalovirus infection in recipients of hematopoietic cell transplantation (HCT). The mouse model of experimental HCT and infection with murine cytomegalovirus revealed that reconstitution of virus-specific CD8+ T cells is critical for resolving productive lung [...] Read more.
Interstitial pneumonia is a life-threatening clinical manifestation of cytomegalovirus infection in recipients of hematopoietic cell transplantation (HCT). The mouse model of experimental HCT and infection with murine cytomegalovirus revealed that reconstitution of virus-specific CD8+ T cells is critical for resolving productive lung infection. CD8+ T-cell infiltrates persisted in the lungs after the establishment of latent infection. A subset defined by the phenotype KLRG1+CD62L expanded over time, a phenomenon known as memory inflation (MI). Here we studied the localization of these inflationary T effector-memory cells (iTEM) by comparing their frequencies in the intravascular and transmigration compartments, the IVC and TMC, respectively, with their frequency in the extravascular compartment (EVC), the alveolar epithelium. Frequencies of viral epitope-specific iTEM were comparable in the IVC and TMC but were reduced in the EVC, corresponding to an increase in KLRG1CD62L conventional T effector-memory cells (cTEM) and a decrease in functional IFNγ+CD8+ T cells. As maintained expression of KLRG1 requires stimulation by antigen, we conclude that iTEM lose KLRG1 and convert to cTEM after transmigration into the EVC because pneumocytes are not latently infected and, therefore, do not express antigens. Accordingly, antigen re-expression upon airway challenge infection recruited virus-specific CD8+ T cells to TMC and EVC. Full article
(This article belongs to the Special Issue Biology of Cytomegalovirus Infection)
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28 pages, 6508 KiB  
Article
Dynamin Inhibitors Prevent the Establishment of the Cytomegalovirus Assembly Compartment in the Early Phase of Infection
by Igor Štimac, Natalia Jug Vučko, Gordana Blagojević Zagorac, Marina Marcelić, Hana Mahmutefendić Lučin and Pero Lučin
Life 2021, 11(9), 876; https://doi.org/10.3390/life11090876 - 25 Aug 2021
Cited by 8 | Viewed by 2588
Abstract
Cytomegalovirus (CMV) infection initiates massive rearrangement of cytoplasmic organelles to generate assembly compartment (AC). The earliest events, the establishment of the preAC, are initiated in the early phase as an extensive reorganization of early endosomes (EEs), endosomal recycling compartment (ERC), trans-Golgi network (TGN), [...] Read more.
Cytomegalovirus (CMV) infection initiates massive rearrangement of cytoplasmic organelles to generate assembly compartment (AC). The earliest events, the establishment of the preAC, are initiated in the early phase as an extensive reorganization of early endosomes (EEs), endosomal recycling compartment (ERC), trans-Golgi network (TGN), and the Golgi. Here, we demonstrate that dynamin inhibitors (Dynasore, Dyngo-4a, MiTMAB, and Dynole-34-2) block the establishment of the preAC in murine CMV (MCMV) infected cells. In this study, we extensively analyzed the effect of Dynasore on the Golgi reorganization sequence into the outer preAC. We also monitored the development of the inner preAC using a set of markers that define EEs (Rab5, Vps34, EEA1, and Hrs), the EE-ERC interface (Rab10), the ERC (Rab11, Arf6), three layers of the Golgi (GRASP65, GM130, Golgin97), and late endosomes (Lamp1). Dynasore inhibited the pericentriolar accumulation of all markers that display EE-ERC-TGN interface in the inner preAC and prevented Golgi unlinking and dislocation to the outer preAC. Furthermore, in pulse-chase experiments, we demonstrated that the presence of dynasore only during the early phase of MCMV infection (4–14 hpi) is sufficient to prevent not only AC formation but also the synthesis of late-phase proteins and virion production. Therefore, our results indicate that dynamin-2 acts as a part of the machinery required for AC generation and rearrangement of EE/ERC/Golgi membranes in the early phase of CMV infection. Full article
(This article belongs to the Special Issue Biology of Cytomegalovirus Infection)
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28 pages, 5406 KiB  
Article
Arf GTPases Are Required for the Establishment of the Pre-Assembly Compartment in the Early Phase of Cytomegalovirus Infection
by Valentino Pavišić, Hana Mahmutefendić Lučin, Gordana Blagojević Zagorac and Pero Lučin
Life 2021, 11(8), 867; https://doi.org/10.3390/life11080867 - 23 Aug 2021
Cited by 5 | Viewed by 2544
Abstract
Shortly after entering the cells, cytomegaloviruses (CMVs) initiate massive reorganization of cellular endocytic and secretory pathways, which results in the forming of the cytoplasmic virion assembly compartment (AC). We have previously shown that the formation of AC in murine CMV- (MCMV) infected cells [...] Read more.
Shortly after entering the cells, cytomegaloviruses (CMVs) initiate massive reorganization of cellular endocytic and secretory pathways, which results in the forming of the cytoplasmic virion assembly compartment (AC). We have previously shown that the formation of AC in murine CMV- (MCMV) infected cells begins in the early phase of infection (at 4–6 hpi) with the pre-AC establishment. Pre-AC comprises membranes derived from the endosomal recycling compartment, early endosomes, and the trans-Golgi network, which is surrounded by fragmented Golgi cisterns. To explore the importance of Arf GTPases in the biogenesis of the pre-AC, we infected Balb 3T3 cells with MCMV and analyzed the expression and intracellular localization of Arf proteins in the early phases (up to 16 hpi) of infection and the development of pre-AC in cells with a knockdown of Arf protein expression by small interfering RNAs (siRNAs). Herein, we show that even in the early phase, MCMVs cause massive reorganization of the Arf system of the host cells and induce the over-recruitment of Arf proteins onto the membranes of pre-AC. Knockdown of Arf1, Arf3, Arf4, or Arf6 impaired the establishment of pre-AC. However, the knockdown of Arf1 and Arf6 also abolished the establishment of infection. Our study demonstrates that Arf GTPases are required for different steps of early cytomegalovirus infection, including the establishment of the pre-AC. Full article
(This article belongs to the Special Issue Biology of Cytomegalovirus Infection)
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27 pages, 53006 KiB  
Article
Endosomal Phosphatidylinositol-3-Phosphate-Associated Functions Are Dispensable for Establishment of the Cytomegalovirus Pre-Assembly Compartment but Essential for the Virus Growth
by Marina Marcelić, Hana Mahmutefendić Lučin, Antonija Jurak Begonja, Gordana Blagojević Zagorac, Vanda Juranić Lisnić and Pero Lučin
Life 2021, 11(8), 859; https://doi.org/10.3390/life11080859 - 22 Aug 2021
Cited by 4 | Viewed by 2519
Abstract
Murine cytomegalovirus (MCMV) initiates the stepwise establishment of the pre-assembly compartment (pre-AC) in the early phase of infection by the expansion of the early endosome (EE)/endosomal recycling compartment (ERC) interface and relocation of the Golgi complex. We depleted Vps34-derived phosphatidylinositol-3-phosphate (PI(3)P) at EEs [...] Read more.
Murine cytomegalovirus (MCMV) initiates the stepwise establishment of the pre-assembly compartment (pre-AC) in the early phase of infection by the expansion of the early endosome (EE)/endosomal recycling compartment (ERC) interface and relocation of the Golgi complex. We depleted Vps34-derived phosphatidylinositol-3-phosphate (PI(3)P) at EEs by VPS34-IN1 and inhibited PI(3)P-associated functions by overexpression of 2xFYVE- and p40PX PI(3)P-binding modules to assess the role of PI(3)P-dependent EE domains in the pre-AC biogenesis. We monitored the accumulation of Rab10 and Evectin-2 in the inner pre-AC and the relocation of GM130-positive cis-Golgi organelles to the outer pre-AC by confocal microscopy. Although PI(3)P- and Vps34-positive endosomes build a substantial part of pre-AC, the PI(3)P depletion and the inhibition of PI(3)P-associated functions did not prevent the establishment of infection and progression through the early phase. The PI(3)P depletion in uninfected and MCMV-infected cells rapidly dispersed PI(3)P-bond proteins and reorganized EEs, including ablation of EE-to-ERC transport and relocation of Rab11 endosomes. The PI(3)P depletion one hour before pre-AC initiation and overexpression of 2xFYVE and p40PX domains neither prevented Rab10- and Evectin-2 accumulation, nor Golgi unlinking and relocation. These data demonstrate that PI(3)P-dependent functions, including the Rab11-dependent EE-to-ERC route, are dispensable for pre-AC initiation. Nevertheless, the virus growth was drastically reduced in PI(3)P-depleted cells, indicating that PI(3)P-associated functions are essential for the late phase of infection. Full article
(This article belongs to the Special Issue Biology of Cytomegalovirus Infection)
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Review

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16 pages, 1246 KiB  
Review
CD8 T Cell Vaccines and a Cytomegalovirus-Based Vector Approach
by Marko Šustić, Maja Cokarić Brdovčak, Astrid Krmpotić and Stipan Jonjić
Life 2021, 11(10), 1097; https://doi.org/10.3390/life11101097 - 15 Oct 2021
Cited by 2 | Viewed by 2669
Abstract
The twentieth century witnessed a huge expansion in the number of vaccines used with great success in combating diseases, especially the ones caused by viral and bacterial pathogens. Despite this, several major public health threats, such as HIV, tuberculosis, malaria, and cancer, still [...] Read more.
The twentieth century witnessed a huge expansion in the number of vaccines used with great success in combating diseases, especially the ones caused by viral and bacterial pathogens. Despite this, several major public health threats, such as HIV, tuberculosis, malaria, and cancer, still pose an enormous humanitarian and economic burden. As vaccines based on the induction of protective, neutralizing antibodies have not managed to effectively combat these diseases, in recent decades, the focus has increasingly shifted towards the cellular immune response. There is substantial evidence demonstrating CD8 T cells as key players in the protection not only against many viral and bacterial pathogens, but also in the fight against neoplastic cells. Here, we present arguments for CD8 T cells to be considered as promising candidates for vaccine targeting. We discuss the heterogeneity of CD8 T cell populations and their contribution in the protection of the host. We also outline several strategies of using a common human pathogen, cytomegalovirus, as a vaccine vector since accumulated data strongly suggest it represents a promising approach to the development of novel vaccines against both pathogens and tumors. Full article
(This article belongs to the Special Issue Biology of Cytomegalovirus Infection)
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