Macrophage and T-Cell Gene Expression in a Model of Early Infection with the Protozoan Leishmania chagasi

• Type of Material: Article
• Authors: Nicholas Ettinger, Emory University; Mary E. Wilson, University of Iowa
• Language: English
• Date: 2008-06-01
• Publisher: PUBLIC LIBRARY SCIENCE
• Publication Version: Final Published Version
• Copyright Statement: This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.pntd.0000252
• Title of Journal or Parent Work: PLOS NEGLECTED TROPICAL DISEASES
• Volume: 2
• Issue: 6
• Start Page: e252
• End Page: e252
• Grant/Funding Information: This work was supported by NIH grants R01 AI045540, R01 AI067874, R01 AI059451, and P50 AI-30639. Work was performed during periods of support for NAE from NIH grants T32 AI07511 and NIGMS MSTP Training Grant T32 GM07337. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
• Keywords: Tropical Medicine; ACTIVATION; Infectious Diseases; BIOCONDUCTOR; RESPONSES; DONOVANI INFECTIONS; INTERLEUKIN-10; Parasitology; HUMAN VISCERAL LEISHMANIASIS; PROFILES; TGF-BETA; Life Sciences & Biomedicine; INTERFERON-GAMMA; Science & Technology; SUPPRESSION
• Research Categories: Health Sciences, Immunology; Biology, Virology

Abstract

Visceral leishmaniasis is a potentially fatal infectious disease caused by the protozoan parasite Leishmania infantum/chagasi in the New World, or by L. donovani or L. infantum/chagasi in the Old World. Infection leads to a variety of outcomes ranging from asymptomatic infection to active disease, characterized by fevers, cachexia, hepatosplenomegaly and suppressed immune responses. We reasoned that events occurring during the initial few hours when the parasite encounters cells of the innate and adaptive immune systems are likely to influence the eventual immune response that develops. Therefore, we performed gene expression analysis using Affymetrix U133Plus2 microarray chips to investigate a model of early infection with human monocyte-derived macrophages (MDMs) challenged with wild-type L. chagasi parasites, with or without subsequent co-culture with Leishmania-naïve, autologous T-cells. Microarray data generated from total RNA were analyzed with software from the Bioconductor Project and functional clustering and pathway analysis were performed with DAVID and Gene Set Enrichment Analysis (GSEA), respectively. Many transcripst were down-regulated by infection in cultures containing macrophages alone, and the pattern indicated a lack of a classically activated phenotype. By contrast, the addition of autologous Leishmania-naïve T cells to infected macrophages resulted in a pattern of gene expression including many markers of type 1 immune cytokine activation (IFN-γ, IL-6, IL-1α, IL-1β). There was simultaneous up-regulation of a few markers of immune modulation (IL-10 cytokine accumulation; TGF-β Signaling Pathway). We suggest that the initial encounter between L. chagasi and cells of the innate and adaptive immune system stimulates primarily type 1 immune cytokine responses, despite a lack of classical macrophage activation. This local microenvironment at the site of parasite inoculation may determine the initial course of immune T-cell development.