title: Leishmania donovani infection causes distinct epigenetic DNA methylation changes in host macrophages.
abstract: Infection of macrophages by the intracellular protozoan Leishmania leads to down-regulation of a number of macrophage innate host defense mechanisms, thereby allowing parasite survival and replication. The underlying molecular mechanisms involved remain largely unknown. In this study, we assessed epigenetic changes in macrophage DNA methylation in response to infection with L. donovani as a possible mechanism for Leishmania driven deactivation of host defense. We quantified and detected genome-wide changes of cytosine methylation status in the macrophage genome resulting from L. donovani infection. A high confidence set of 443 CpG sites was identified with changes in methylation that correlated with live L. donovani infection. These epigenetic changes affected genes that play a critical role in host defense such as the JAK/STAT signaling pathway and the MAPK signaling pathway. These results provide strong support for a new paradigm in host-pathogen responses, where upon infection the pathogen induces epigenetic changes in the host cell genome resulting in downregulation of innate immunity thereby enabling pathogen survival and replication. We therefore propose a model whereby Leishmania induced epigenetic changes result in permanent down regulation of host defense mechanisms to protect intracellular replication and survival of parasitic cells.
authors.affiliation: Immunity and Infection Research Centre, Vancouver Coastal Health Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
authors.forename: Alexandra K
authors.initials: AK
authors.lastname: Marr
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
authors.forename: Julia L
authors.initials: JL
authors.lastname: MacIsaac
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
authors.forename: Ruiwei
authors.initials: R
authors.lastname: Jiang
authors.affiliation: Immunity and Infection Research Centre, Vancouver Coastal Health Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
authors.forename: Adriana M
authors.initials: AM
authors.lastname: Airo
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, Canada; Human Early Learning Partnership, School of Population and Public Health, Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Kobor
authors.affiliation: Immunity and Infection Research Centre, Vancouver Coastal Health Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
authors.forename: W Robert
authors.initials: WR
authors.lastname: McMaster
mesh_terms: D019175:DNA Methylation / Q000276:immunology*; D044127:Epigenesis, Genetic / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D007893:Leishmania donovani; D007898:Leishmaniasis, Visceral / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000382:microbiology*; D015398:Signal Transduction / Q000276:immunology