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.

Author Summary

The L. donovani parasite causes visceral leishmaniasis, a tropical, neglected disease with an estimated number of 500,000 cases worldwide. Current drug treatments have toxic side effects, lead to drug resistance, and an effective vaccine is not available. The parasite has a complex life cycle residing within different host environments including the gut of a sand fly and immune cells of the mammalian host. Alteration of host cell gene expression including signaling pathways has been shown to be a major strategy to evade host cell immune response and thus enables the Leishmania parasite to survive, replicate and persist in its host cells. Recently it was demonstrated that intracellular pathogens such as viruses and bacteria are able to manipulate epigenetic processes, thereby perhaps facilitating their intracellular survival. Using an unbiased genome-wide DNA methylation approach, we demonstrate here that an intracellular parasite can alter host cell DNA methylation patterns resulting in altered gene expression possibly to establish disease. Thus DNA methylation changes in host cells upon infection might be a common strategy among intracellular pathogens for their uncontrolled replication and dissemination.