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Differential cellular localization of Epstein–Barr virus and human cytomegalovirus in the colonic mucosa of patients with active or quiescent inflammatory bowel disease

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Abstract

The role of human cytomegalovirus (HCMV) and Epstein–Barr virus (EBV) in the exacerbation of inflammatory bowel disease (IBD) is still uncertain. We prospectively investigated the presence of EBV and HCMV infection in both epithelial and immune cells of colonic mucosa of IBD patients, both refractory and responders to standard therapies, in comparison with patients suffering from irritable bowel syndrome who were considered as controls, by using quantitative real-time polymerase chain reaction, immunohistochemistry and in situ hybridization, in an attempt to assess viral localization, DNA load, life cycle phase and possible correlation with disease activity indexes. We obtained clear evidence of the presence of high DNA loads of both viruses in either enterocytes or immune cells of refractory IBD patients, whereas we observed low levels in the responder group and an absence of detectable copies in all cell populations of controls. Remarkably, the values of EBV and HCMV DNA in inflamed mucosa were invariably higher than in non-inflamed areas in both IBD groups, and the EBV DNA loads in the cell populations of diseased mucosa of refractory IBD patients positively correlated with the severity of mucosal damage and clinical indexes of activity. Moreover, EBV infection resulted the most prevalent either alone or in combination with HCMV, while immunohistochemistry and in situ hybridization did not allow us to distinguish between the different phases of viral life cycle. Finally, as regards treatment, these novel findings could pave the way for the use of new antiviral molecules in the treatment of this condition.

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Abbreviations

CD:

Crohn’s disease

CDAI:

Crohn’s Disease Activity Index

CDEIS:

Crohn’s Disease Endoscopic Index of Severity

EBV:

Epstein–Barr virus

EBER:

EBV-encoded RNAs

HCMV:

Human cytomegalovirus

FITC:

Fluorescein isothiocyanate

IBD:

Inflammatory bowel disease

ISH:

In situ hybridization

IQR:

Interquartile range

IELs:

Intraepithelial lymphocytes

LPMCs:

Lamina propria mononuclear cells

Real-time PCR:

Real-time polymerase chain reaction

SCCAI:

Simple Clinical Colitis Activity Index

UC:

Ulcerative colitis

UCEIS:

Ulcerative Colitis Endoscopic Index of Severity

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Acknowledgments

The authors are grateful to Ms. Sheila McVeigh for her thorough revision of the English text. Furthermore, RR is a recipient of a Grant (Project #580) from the Italian Ministry of Health (5 per Mille) of the Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; AV is recipient of a fellowship from the Anatomic Pathology Section, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

Financial support

This study was financed in part by the Fondazione IRCCS Policlinico San Matteo (Progetto di Ricerca Corrente) entitled: “Studio dell’infezione da Citomegalovirus umano ed Epstein–Barr virus nelle malattie infiammatorie croniche intestinali” (Project No. 821; Code: 08064415). The sponsor had no role in the study design, collection, analysis or interpretation of the data, writing of the manuscript, nor in the decision to submit the paper for publication.

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Authors and Affiliations

  1. Department of Internal Medicine, IRCCS Policlinico San Matteo Foundation, University of Pavia, Piazzale Golgi, 19, 27100, Pavia, Italy

    Rachele Ciccocioppo, Francesca Racca, Pietro Formagnana, Lodovica Pozzi, Elena Betti & Gino Roberto Corazza

  2. Biometry and Clinical Epidemiology Unit, IRCCS Policlinico San Matteo Foundation, Pavia, Italy

    Luigia Scudeller

  3. SS Virologia Molecolare - SC Virologia e Microbiologia, IRCCS Policlinico San Matteo Foundation, Pavia, Italy

    Antonio Piralla & Fausto Baldanti

  4. Department of Human Pathology, IRCCS Policlinico San Matteo Foundation, Pavia, Italy

    Alessandro Vanoli & Roberta Riboni

  5. 2nd Department of Internal Medicine, St. Anne’s University Hospital and Masaryk University, Pekarska 53, 656 91, Brno, Czech Republic

    Peter Kruzliak

  6. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Odborarov 10, 832 32, Bratislava, Slovak Republic

    Peter Kruzliak

  7. Department of Clinical Sciences, Surgery, Diagnostics and Pediatrics, University of Pavia, Pavia, Italy

    Fausto Baldanti

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  1. Rachele Ciccocioppo
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  2. Francesca Racca
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  3. Luigia Scudeller
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  4. Antonio Piralla
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  7. Elena Betti
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  8. Alessandro Vanoli
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  9. Roberta Riboni
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  10. Peter Kruzliak
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  11. Fausto Baldanti
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  12. Gino Roberto Corazza
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Correspondence to Rachele Ciccocioppo or Peter Kruzliak.

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Ciccocioppo, R., Racca, F., Scudeller, L. et al. Differential cellular localization of Epstein–Barr virus and human cytomegalovirus in the colonic mucosa of patients with active or quiescent inflammatory bowel disease. Immunol Res 64, 191–203 (2016). https://doi.org/10.1007/s12026-015-8737-y

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