Leishmania donovani infection causes distinct epigenetic DNA methylation changes in host macrophages.

Alexandra K Marr,Julia L Macisaac,Michael S Kobor,W Robert Mcmaster,Ruiwei Jiang,Adriana M Airo,David Horn

doi:10.1371/journal.ppat.1004419

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.

Highlights

Leishmania parasites have a complex life cycle usually alternating between an insect vector and a vertebrate host, or between vertebrate hosts
To evaluate epigenetic changes in host cells caused by infection with a protozoan parasite, DNA methylation of genomic DNA from human macrophages infected with L. donovani was studied
To differentiate among changes induced by Leishmania infection versus those triggered by phagocytosis, macrophages treated with heat killed L. donovani promastigotes, as well as uninfected macrophages were used as controls

Summary

Introduction

Leishmania parasites have a complex life cycle usually alternating between an insect vector and a vertebrate host, or between vertebrate hosts. Essential macrophage activation signaling molecules and pathways such as PKC, JAK/STAT, MAPK, NF-kB as well as the transcription factor AP-1 are deactivated following infection with Leishmania [7]. Molecules such as SHP-1 are activated during Leishmania infection causing SHP-1 mediated JAK2 inactivation in macrophages [7]. Leishmania evolved several strategies to inhibit macrophage activation, the ability to present antigens on their surface as well as to interfere the communication of macrophages with cells from the adaptive immune system [7]

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Conclusion