Mouse mammary tumor virus is implicated in severity of colitis and dysbiosis in the IL-10−/− mouse model of inflammatory bowel disease

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dc.contributor.authorArmstrong, Heather
dc.contributor.authorRahbari, Mandana
dc.contributor.authorPark, Heekuk
dc.contributor.authorSharon, David
dc.contributor.authorThiesen, Aducio
dc.contributor.authorHotte, Naomi
dc.contributor.authorSun, Ning
dc.contributor.authorSyed, Hussain
dc.contributor.authorAbofayed, Hiatem
dc.contributor.authorWang, Weiwei
dc.contributor.authorMadsen, Karen
dc.contributor.authorWine, Eytan
dc.contributor.authorMason, Andrew
dc.date.accessioned2023-05-01T15:44:43Z
dc.date.available2023-05-01T15:44:43Z
dc.date.issued2023-03-03
dc.date.updated2023-04-04T17:42:38Z
dc.description.abstractAbstract Background Following viral infection, genetically manipulated mice lacking immunoregulatory function may develop colitis and dysbiosis in a strain-specific fashion that serves as a model for inflammatory bowel disease (IBD). We found that one such model of spontaneous colitis, the interleukin (IL)-10 knockout (IL-10−/−) model derived from the SvEv mouse, had evidence of increased Mouse mammary tumor virus (MMTV) viral RNA expression compared to the SvEv wild type. MMTV is endemic in several mouse strains as an endogenously encoded Betaretrovirus that is passaged as an exogenous agent in breast milk. As MMTV requires a viral superantigen to replicate in the gut-associated lymphoid tissue prior to the development of systemic infection, we evaluated whether MMTV may contribute to the development of colitis in the IL-10−/− model. Results Viral preparations extracted from IL-10−/− weanling stomachs revealed augmented MMTV load compared to the SvEv wild type. Illumina sequencing of the viral genome revealed that the two largest contigs shared 96.4–97.3% identity with the mtv-1 endogenous loci and the MMTV(HeJ) exogenous virus from the C3H mouse. The MMTV sag gene cloned from IL-10−/− spleen encoded the MTV-9 superantigen that preferentially activates T-cell receptor Vβ-12 subsets, which were expanded in the IL-10−/− versus the SvEv colon. Evidence of MMTV cellular immune responses to MMTV Gag peptides was observed in the IL-10−/− splenocytes with amplified interferon-γ production versus the SvEv wild type. To address the hypothesis that MMTV may contribute to colitis, we used HIV reverse transcriptase inhibitors, tenofovir and emtricitabine, and the HIV protease inhibitor, lopinavir boosted with ritonavir, for 12-week treatment versus placebo. The combination antiretroviral therapy with known activity against MMTV was associated with reduced colonic MMTV RNA and improved histological score in IL-10−/− mice, as well as diminished secretion of pro-inflammatory cytokines and modulation of the microbiome associated with colitis. Conclusions This study suggests that immunogenetically manipulated mice with deletion of IL-10 may have reduced capacity to contain MMTV infection in a mouse-strain-specific manner, and the antiviral inflammatory responses may contribute to the complexity of IBD with the development of colitis and dysbiosis. Video Abstracten_US
dc.identifier.citationMicrobiome. 2023 Mar 03;11(1):39
dc.identifier.citationMicrobiome. 2023 Mar 03;11(1):39
dc.identifier.urihttps://doi.org/10.1186/s40168-023-01483-4
dc.identifier.urihttp://hdl.handle.net/1993/37317
dc.language.isoengen_US
dc.language.rfc3066en
dc.publisherBioMed Central (BMC)en_US
dc.rightsopen accessen_US
dc.rights.holderThe Author(s)
dc.titleMouse mammary tumor virus is implicated in severity of colitis and dysbiosis in the IL-10−/− mouse model of inflammatory bowel diseaseen_US
dc.typejournal articleen_US
local.author.affiliationRady Faculty of Health Sciences::Max Rady College of Medicine::Department of Internal Medicineen_US
oaire.citation.issue1en_US
oaire.citation.startPage39en_US
oaire.citation.titleMicrobiomeen_US
oaire.citation.volume11en_US
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