title: A B-cell targeting virus disrupts potentially protective genomic methylation patterns in lymphoid tissue by increasing global 5-hydroxymethylcytosine levels.
abstract: The mechanisms by which viruses modulate the immune system include changes in host genomic methylation. 5-hydroxymethylcytosine (5hmC) is the catalytic product of the Tet (Ten-11 translocation) family of enzymes and may serve as an intermediate of DNA demethylation. Recent reports suggest that 5hmC may confer consequences on cellular events including the pathogenesis of disease; in order to explore this possibility further we investigated both 5-methylcytosine (5mC) and 5hmC levels in healthy and diseased chicken bursas of Fabricius. We discovered that embryonic B-cells have high 5mC content while 5hmC decreases during bursa development. We propose that a high 5mC level protects from the mutagenic activity of the B-cell antibody diversifying enzyme activation induced deaminase (AID). In support of this view, AID mRNA increases significantly within the developing bursa from embryonic to post hatch stages while mRNAs that encode Tet family members 1 and 2 reduce over the same period. Moreover, our data revealed that infectious bursal disease virus (IBDV) disrupts this genomic methylation pattern causing a global increase in 5hmC levels in a mechanism that may involve increased Tet 1 and 2 mRNAs. To our knowledge this is the first time that a viral infection has been observed to cause global increases in genomic 5hmC within infected host tissues, underlining a mechanism that may involve the induction of B-cell genomic instability and cell death to facilitate viral egress.
authors.affiliation: Avian Viral Diseases (AVD), Compton Laboratory, The Pirbright Institute, Compton, Berkshire, RG20 7NN, UK. nick.ciccone@pirbright.ac.uk.
authors.forename: Nick A
authors.initials: NA
authors.lastname: Ciccone
authors.affiliation: Avian Viral Diseases (AVD), Compton Laboratory, The Pirbright Institute, Compton, Berkshire, RG20 7NN, UK. william.mwangi@pirbright.ac.uk.
authors.forename: William
authors.initials: W
authors.lastname: Mwangi
authors.affiliation: Wolfson Centre for Stem Cells, Tissue Engineering and Modelling (STEM), Division of Cancer and Stem Cells, School of Medicine, Centre for Biomolecular Sciences, University of Nottingham, University Park, Nottingham, NG7 2RD, UK. alexey.ruzov@nottingham.ac.uk.
authors.forename: Alexey
authors.initials: A
authors.lastname: Ruzov
authors.affiliation: Avian Viral Diseases (AVD), Compton Laboratory, The Pirbright Institute, Compton, Berkshire, RG20 7NN, UK. lorraine-p.smith@pirbright.ac.uk.
authors.forename: Lorraine P
authors.initials: LP
authors.lastname: Smith
authors.affiliation: Avian Viral Diseases (AVD), Compton Laboratory, The Pirbright Institute, Compton, Berkshire, RG20 7NN, UK. colin.butter@pirbright.ac.uk.
authors.forename: Colin
authors.initials: C
authors.lastname: Butter
authors.affiliation: Avian Viral Diseases (AVD), Compton Laboratory, The Pirbright Institute, Compton, Berkshire, RG20 7NN, UK. venugopal.nair@pirbright.ac.uk.
authors.forename: Venugopal
authors.initials: V
authors.lastname: Nair
mesh_terms: D044503:5-Methylcytosine / Q000378:metabolism* / Q000031:analogs & derivatives; D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology; D018175:Birnaviridae Infections / Q000276:immunology / Q000378:metabolism / Q000662:veterinary* / Q000821:virology; D002060:Bursa of Fabricius / Q000276:immunology / Q000378:metabolism; D002645:Chickens; D003596:Cytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D019175:DNA Methylation; D016678:Genome; D007243:Infectious bursal disease virus / Q000502:physiology; D011201:Poultry Diseases / Q000276:immunology* / Q000378:metabolism / Q000821:virology
chemical_list: C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine