Gene expression profiling of suppressor mechanisms in tuberculosis
Mieneke G A Smit van Dixhoorn1, Riffat Munir, Garth Sussman
1Department of Immunology, School of Pathology, National Health Laboratory Service & University of the Witwatersrand, 1 Hospital Street, Hospital Hill, Johannesburg, South Africa. mieneke.smit@nhls.ac.za <mieneke.smit@nhls.ac.za>
Molecular Immunology
|December 11, 2007
Summary
Mycobacterium tuberculosis (M.tb) infection suppresses protective T helper 1 responses by inducing suppressor carbohydrates (SC). This study identified genes and pathways involved in M.tb immune evasion, offering targets for new therapies.
Area of Science:
- Immunology
- Molecular Biology
- Infectious Diseases
Background:
- Mycobacterium tuberculosis (M.tb) causes millions of deaths annually and manipulates host immune responses.
- Suppressor carbohydrates (SC) from CD8+ T cells induce a T helper 2 (Th2) response instead of a protective T helper 1 (Th1) response in M.tb-infected individuals.
Purpose of the Study:
- To identify genes modulating the T helper response during M.tb infection.
- To elucidate the functions of these genes and their role in M.tb pathogenesis.
- To propose a model for M.tb immune evasion mechanisms.
Main Methods:
- Gene expression profiling of 18,861 genes in human mononuclear (MN) cells pulsed with SC using micro-array analysis.
- Gene Ontology (GO) enrichment analysis to identify significantly modulated pathways.
- Quantitative Real-Time Polymerase Chain Reaction (QRT-PCR) for validation.
Main Results:
- Twenty-eight genes were upregulated and 60 genes were downregulated in response to SC (FDR=1%, fold change>1.4).
- MIP3 alpha and platelet factor 4 (v1) were significantly enriched in the "chemokine activity" GO category.
- Repressed genes were over-represented in GO terms including "response to pathogenic bacteria", "inflammatory response", "coagulation", and "apoptosis", with SC reducing CD4+ T cell numbers and proliferation.
Conclusions:
- M.tb infection, via SC, may induce unresponsiveness in a subset of CD4+ T cells.
- Monocytes appear to provide an immunomodulatory signal to CD4+ T cells during M.tb infection.
- These findings provide insights for developing novel therapeutics to restore protective Th1 responses against M.tb.
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