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Beta-Herpesvirus Infection and Possible Cooperation in the Pathogenesis of Autoimmune...
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Beta-Herpesvirus Infection and Possible Cooperation in the Pathogenesis of Autoimmune Diseases

A special issue of Microorganisms (ISSN 2076-2607). This special issue belongs to the section "Medical Microbiology".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 14346

Special Issue Editors

Prof. Dr. Maria-Cristina Arcangeletti

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Guest Editor
Department of Medicine and Surgery, University of Parma; Unit of Virology, University-Hospital of Parma, Parma, Italy
Interests: human cytomegalovirus infection and virulence factors; human beta-herpesvirus infection; pathogenic mechanisms and disease correlation; beta-herpesvirus and autoimmune diseases
Prof. Dr. Elisabetta Caselli

E-Mail Website
Guest Editor
Department of Chemical, Pharmaceutical and Agricultural Sciences, Section of Microbiology, University of Ferrara, 44121 Ferrara, Italy
Interests: human herpesvirus 6 and human beta-herpesvirus infection; pathogenesis and disease association; autoimmune diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The pathogenesis of several autoimmune diseases remains largely unknown; however, accumulating evidence suggests that autoimmune disorders could be the result of multifactorial processes. Among the involved/predisposing factors, persistent/latent viral infections, such as human cytomegalovirus (HCMV) and human herpesvirus 6 (HHV-6) infections, have been suggested as possibly being involved in the pathogenesis of a number of autoimmune diseases. Both viruses belong to the Betaherpesvirinae subfamily of the Herpesviridae family, are genetically related, have a common tropism and pathogenic characteristics and have a worldwide distribution, with primary infection usually being sustained early in life and then establishing a latent lifelong infection in the host. It is known that HCMV and HHV-6 can interact by reactivating each other, so that one virus may potentiate the effect of the other virus in coinfected patients. Thus, it might be hypothesized that in subjects with impaired ability to control herpesvirus infection/reactivation, the simultaneous presence of both viruses might lead to even worse effects compared to those resulting from a single infection. Studies on human herpesvirus 7 (HHV-7), a beta-herpesvirus belonging to the Roseolovirus genus (as HHV-6) but still lacking pathogenic association with a specific disease, would be also needed to improve and deepen the current knowledge about the potential of beta-herpesvirus in the development of autoimmune diseases.

This Special Issue aims to expand the knowledge on the role of beta-herpesvirus, also considering possible cooperation, in the pathogenesis of specific autoimmune diseases and the contribution of potential underlying mechanisms triggering the development of these disorders, also opening new perspectives about the potential therapeutic use of antiherpetic drugs able to block illness progression.

Research articles, communications and reviews are welcome.

Prof. Dr. Maria-Cristina Arcangeletti
Prof. Dr. Elisabetta Caselli
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. Microorganisms 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 2700 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

  • beta-herpesvirus and autoimmune disease pathogenesis
  • human cytomegalovirus
  • human herpesvirus 6
  • virus cooperation

Published Papers (6 papers)

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Editorial

Jump to: Research

3 pages, 191 KiB  
Editorial
Recent Advances in Unveiling the Role of Beta-Herpesviruses in Autoimmune Diseases
by Maria Cristina Arcangeletti and Elisabetta Caselli
Microorganisms 2021, 9(12), 2572; https://doi.org/10.3390/microorganisms9122572 - 13 Dec 2021
Cited by 2 | Viewed by 1873
Abstract
A dysregulated immune response can lead to recognition of self-antigens as non-self-antigens, leading to failure of the immune tolerance toward normal cells and tissues, and the consequent development of a variety of autoimmune diseases [...] Full article
(This article belongs to the Special Issue Beta-Herpesvirus Infection and Possible Cooperation in the Pathogenesis of Autoimmune Diseases)

Research

Jump to: Editorial

15 pages, 1892 KiB  
Article
Coinfection of Dermal Fibroblasts by Human Cytomegalovirus and Human Herpesvirus 6 Can Boost the Expression of Fibrosis-Associated MicroRNAs
by Irene Soffritti, Maria D’Accolti, Clara Maccari, Francesca Bini, Eleonora Mazziga, Maria-Cristina Arcangeletti and Elisabetta Caselli
Microorganisms 2023, 11(2), 412; https://doi.org/10.3390/microorganisms11020412 - 06 Feb 2023
Viewed by 1429
Abstract
Tissue fibrosis can affect every type of tissue or organ, often leading to organ malfunction; however, the mechanisms involved in this process are not yet clarified. A role has been hypothesized for Human Cytomegalovirus (HCMV) and Human Herpesvirus 6 (HHV-6) infections as triggers [...] Read more.
Tissue fibrosis can affect every type of tissue or organ, often leading to organ malfunction; however, the mechanisms involved in this process are not yet clarified. A role has been hypothesized for Human Cytomegalovirus (HCMV) and Human Herpesvirus 6 (HHV-6) infections as triggers of systemic sclerosis (SSc), a severe autoimmune disease causing progressive tissue fibrosis, since both viruses and antiviral immune responses toward them have been detected in patients. Moreover, HCMV or HHV-6A infection was reported to increase the expression of fibrosis-associated transcriptional factors and miRNAs in human dermal fibroblasts. However, it is unlikely that they have separate effects in the infected host, as both viruses are highly prevalent in the human population. Thus, our study aimed to investigate, by quantitative real-time PCR microarray, the impact of HCMV/HHV-6A coinfection on the expression of pro-fibrotic miRNAs in coinfected cells, compared to the effect of single viruses. The results showed a possible synergistic effect of the two viruses on pro-fibrotic miRNA expression, thus suggesting that HCMV and HHV-6 may enhance each other and cooperate at inducing enhanced miRNA-driven fibrosis. These data may also suggest a possible use of virus-induced miRNAs as novel diagnostic or prognostic biomarkers for SSc and its clinical treatment. Full article
(This article belongs to the Special Issue Beta-Herpesvirus Infection and Possible Cooperation in the Pathogenesis of Autoimmune Diseases)
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15 pages, 1059 KiB  
Article
Herpesvirus Screening in Childhood Hematopoietic Transplant Reveals High Systemic Inflammation in Episodes of Multiple Viral Detection and an EBV Association with Elevated IL-1β, IL-8 and Graft-Versus-Host Disease
by Moisés H. Rojas-Rechy, Félix Gaytán-Morales, Yessica Sánchez-Ponce, Iván Castorena-Villa, Briceida López-Martínez, Israel Parra-Ortega, María C. Escamilla-Núñez, Alfonso Méndez-Tenorio, Ericka N. Pompa-Mera, Gustavo U. Martinez-Ruiz, Ezequiel M. Fuentes-Pananá and Abigail Morales-Sánchez
Microorganisms 2022, 10(8), 1685; https://doi.org/10.3390/microorganisms10081685 - 22 Aug 2022
Cited by 3 | Viewed by 2015
Abstract
Infections remain a major cause of morbidity and mortality among hematopoietic stem cell transplant (HSCT) recipients. Unlike Epstein–Barr Virus (EBV) and Human Cytomegalovirus (HCMV), Human Herpesvirus (HHV) 6, HHV7 and HHV8 are not routinely monitored in many centers, especially in the pediatric population [...] Read more.
Infections remain a major cause of morbidity and mortality among hematopoietic stem cell transplant (HSCT) recipients. Unlike Epstein–Barr Virus (EBV) and Human Cytomegalovirus (HCMV), Human Herpesvirus (HHV) 6, HHV7 and HHV8 are not routinely monitored in many centers, especially in the pediatric population of low–medium income countries. We screened EBV, HCMV, HHV6, HHV7 and HHV8 in 412 leukocytes-plasma paired samples from 40 pediatric patients assisted in a tertiary hospital in Mexico. Thirty-two underwent allo-HSCT, whereas eight received auto-HSCT. Overall viral detection frequencies in allo- and auto-HSCT were: EBV = 43.7% and 30.0%, HCMV = 5.0% and 6.7%, HHV6 = 7.9% and 20.0% and HHV7 = 9.7% and 23.3%. HHV8 was not detected in any sample. Interestingly, HHV6 and HHV7 were more frequent in auto-HSCT, and HHV6 was observed in all episodes of multiple detection in auto-HSCT patients. We found EBV DNA in plasma samples, whereas HCMV, HHV6 and HHV7 DNA were predominantly observed in leukocytes, indicative of their expansion in cellular compartments. We also found that IL-1β, IL-2, IL-6 and IL-8 were significantly increased in episodes in which multiple viruses were simultaneously detected, and samples positive for EBV DNA and graft-versus-host disease had a further increase of IL-1β and IL-8. In conclusion, the EBV, HCMV, HHV6 and HHV7 burdens were frequently detected in allo- and auto-HSCT, and their presence associated with systemic inflammation. Full article
(This article belongs to the Special Issue Beta-Herpesvirus Infection and Possible Cooperation in the Pathogenesis of Autoimmune Diseases)
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16 pages, 2560 KiB  
Article
Human Cytomegalovirus and Human Herpesvirus 6 Coinfection of Dermal Fibroblasts Enhances the Pro-Inflammatory Pathway Predisposing to Fibrosis: The Possible Impact on Systemic Sclerosis
by Irene Soffritti, Maria D’Accolti, Clara Maccari, Francesca Bini, Eleonora Mazziga, Flora de Conto, Adriana Calderaro, Maria-Cristina Arcangeletti and Elisabetta Caselli
Microorganisms 2022, 10(8), 1600; https://doi.org/10.3390/microorganisms10081600 - 08 Aug 2022
Cited by 2 | Viewed by 2101
Abstract
Systemic sclerosis (SSc) is a severe autoimmune disease likely triggered by genetic and environmental factors, including viral infections. Human cytomegalovirus (HCMV) and human herpesvirus 6A species (HHV-6A) have been associated with SSc, based on in vivo and in vitro evidence, but the data [...] Read more.
Systemic sclerosis (SSc) is a severe autoimmune disease likely triggered by genetic and environmental factors, including viral infections. Human cytomegalovirus (HCMV) and human herpesvirus 6A species (HHV-6A) have been associated with SSc, based on in vivo and in vitro evidence, but the data are still inconclusive. Furthermore, despite both viruses being highly prevalent in humans and able to exacerbate each other’s effects, no data are available on their joint effects. Hence, we aimed to study their simultaneous impact on the expression of cell factors correlated with fibrosis and apoptosis in in vitro coinfected fibroblasts, representing the main target cell type in SSc. The results, obtained by a microarray detecting 84 fibrosis/apoptosis-associated factors, indicated that coinfected cells underwent higher and more sustained expression of fibrosis-associated parameters compared with single-infected cells. Thus, the data, for the first time, suggest that HCMV and HHV-6A may cooperate in inducing alterations potentially leading to cell fibrosis, thus further supporting their joint role in SSc. However, further work is required to definitively answer whether β-herpesviruses are causally linked to the disease and to enable the possible use of targeted antiviral treatments to improve clinical outcomes. Full article
(This article belongs to the Special Issue Beta-Herpesvirus Infection and Possible Cooperation in the Pathogenesis of Autoimmune Diseases)
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15 pages, 2713 KiB  
Article
Herpesvirus Infections in KIR2DL2-Positive Multiple Sclerosis Patients: Mechanisms Triggering Autoimmunity
by Daria Bortolotti, Valentina Gentili, Alessandra Bortoluzzi, Marcello Govoni, Giovanna Schiuma, Silvia Beltrami, Sabrina Rizzo, Eleonora Baldi, Elisabetta Caselli, Maura Pugliatti, Massimiliano Castellazzi, Mercedes Fernández, Enrico Fainardi and Roberta Rizzo
Microorganisms 2022, 10(3), 494; https://doi.org/10.3390/microorganisms10030494 - 23 Feb 2022
Cited by 1 | Viewed by 2185
Abstract
In multiple sclerosis (MS), there is a possible relationship with viral infection, evidenced by clinical evidence of an implication of infectious events with disease onset and/or relapse. The aim of this research is to study how human herpesvirus (HHVs) infections might dysregulate the [...] Read more.
In multiple sclerosis (MS), there is a possible relationship with viral infection, evidenced by clinical evidence of an implication of infectious events with disease onset and/or relapse. The aim of this research is to study how human herpesvirus (HHVs) infections might dysregulate the innate immune system and impact autoimmune responses in MS. We analyzed 100 MS relapsing remitting patients, in the remission phase, 100 healthy controls and 100 subjects with other inflammatory neurological diseases (OIND) (neuro-lupus) for their immune response to HHV infection. We evaluated NK cell response, levels of HHVs DNA, IgG and pro- and anti-inflammatory cytokines. The results demonstrated that the presence of KIR2DL2 expression on NK cells increased the susceptibility of MS patients to HHV infections. We showed an increased susceptibility mainly to EBV and HHV-6 infections in MS patients carrying the KIR2DL2 receptor and HLA-C1 ligand. The highest HHV-6 viral load was observed in MS patients, with an increased percentage of subjects positive for IgG against HHV-6 in KIR2DL2-positive MS and OIND subjects compared to controls. MS and OIND patients showed the highest levels of IL-8, IL-12p70, IL-10 and TNF-alpha in comparison with control subjects. Interestingly, MS and OIND patients showed similar levels of IL-8, while MS patients presented higher IL-12p70, TNF-alpha and IL-10 levels in comparison with OIND patients. We can hypothesize that HHVs’ reactivation, by inducing immune activation via also molecular mimicry, may have the ability to induce autoimmunity and cause tissue damage and consequent MS lesion development. Full article
(This article belongs to the Special Issue Beta-Herpesvirus Infection and Possible Cooperation in the Pathogenesis of Autoimmune Diseases)
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12 pages, 465 KiB  
Article
Herpes Simplex Virus Re-Activation in Patients with SARS-CoV-2 Pneumonia: A Prospective, Observational Study
by Erica Franceschini, Alessandro Cozzi-Lepri, Antonella Santoro, Erica Bacca, Guido Lancellotti, Marianna Menozzi, William Gennari, Marianna Meschiari, Andrea Bedini, Gabriella Orlando, Cinzia Puzzolante, Margherita Digaetano, Jovana Milic, Mauro Codeluppi, Monica Pecorari, Federica Carli, Gianluca Cuomo, Gaetano Alfano, Luca Corradi, Roberto Tonelli, Nicola De Maria, Stefano Busani, Emanuela Biagioni, Irene Coloretti, Giovanni Guaraldi, Mario Sarti, Mario Luppi, Enrico Clini, Massimo Girardis, Inge C. Gyssens and Cristina Mussiniadd Show full author list remove Hide full author list
Microorganisms 2021, 9(9), 1896; https://doi.org/10.3390/microorganisms9091896 - 07 Sep 2021
Cited by 25 | Viewed by 3580
Abstract
Background: Herpes simplex 1 co-infections in patients with COVID-19 are considered relatively uncommon; some reports on re-activations in patients in intensive-care units were published. The aim of the study was to analyze herpetic re-activations and their clinical manifestations in hospitalized COVID-19 patients, performing [...] Read more.
Background: Herpes simplex 1 co-infections in patients with COVID-19 are considered relatively uncommon; some reports on re-activations in patients in intensive-care units were published. The aim of the study was to analyze herpetic re-activations and their clinical manifestations in hospitalized COVID-19 patients, performing HSV-1 PCR on plasma twice a week. Methods: we conducted a prospective, observational, single-center study involving 70 consecutive patients with severe/critical SARS-CoV-2 pneumonia tested for HSV-1 hospitalized at Azienda Ospedaliero-Universitaria of Modena. Results: of these 70 patients, 21 (30.0%) showed detectable viremia and 13 (62%) had clinically relevant manifestations of HSV-1 infection corresponding to 15 events (4 pneumonia, 5 herpes labialis, 3 gingivostomatitis, one encephalitis and two hepatitis). HSV-1 positive patients were more frequently treated with steroids than HSV-1 negative patients (76.2% vs. 49.0%, p = 0.036) and more often underwent mechanical ventilation (IMV) (57.1% vs. 22.4%, p = 0.005). In the unadjusted logistic regression analysis, steroid treatment, IMV, and higher LDH were significantly associated with an increased risk of HSV1 re-activation (odds ratio 3.33, 4.61, and 16.9, respectively). The association with the use of steroids was even stronger after controlling for previous use of both tocilizumab and IMV (OR = 5.13, 95% CI:1.36–19.32, p = 0.016). The effect size was larger when restricting to participants who were treated with high doses of steroids while there was no evidence to support an association with the use of tocilizumab Conclusions: our study shows a high incidence of HSV-1 re-activation both virologically and clinically in patients with SARS-CoV-2 severe pneumonia, especially in those treated with steroids. Full article
(This article belongs to the Special Issue Beta-Herpesvirus Infection and Possible Cooperation in the Pathogenesis of Autoimmune Diseases)
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