Gene expression profiling of suppressor mechanisms in tuberculosis.
Mycobacterium tuberculosis (M.tb) infects 8 million and kills 2.2 million people each year worldwide. M.tb modulates the immune response of the infected individual. Empirically, suppressor carbohydrates (SC) produced by CD8+ T cells in response to M.tb were found to induce a T helper 2 response rather than a protective T helper 1 response in human mononuclear (MN) cells. This study (1) identifies the genes that modulate the T helper response, (2) describes their function, and (3) postulates a detailed model for the M.tb infection mechanism. MN cells from five healthy donors were pulsed with SC and gene expression profiles of 18,861 genes were assessed in a micro-array experiment. Twenty-eight genes were found to be increased and 60 genes were decreased (FDR=1%, fold change>1.4) in response to SC. MIP3 alpha and platelet factor 4 (v1) are both significantly enriched (p< or =0.001) in the GO category "chemokine activity". Repressed genes were significantly (p< or =0.001) over-represented in the GO terms "response to pathogenic bacteria", "inflammatory response", "coagulation" and "apoptosis". Indeed, SC significantly reduced numbers of Annexin V/CD4+ cells, while inducing hypoproliferation in CD4+ and non-adherent lymphocytes. This may indicate that M.tb renders a portion of the CD4+ T cell population unresponsive. Furthermore, validating QRT-PCR analysis suggests that monocytes provide an immuno-modulatory signal to CD4+ T cells in M.tb infection. These observations will allow development of new therapeutic interventions to restore the desired T helper 1 response.
Smit van Dixhoorn
Mieneke G A
MG
Department 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>
Munir
Riffat
R
Sussman
Garth
G
Stad
Robert
R
de Haan
Muus
M
van der Hoeven
Tessa
T
Rauwerda
Han
H
Breit
Timo M
TM
Thallinger
Gerhard G
GG
Wadee
Ahmed A
AA
D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D066298:In Vitro Techniques; D009000:Monocytes / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000502:physiology*; D013491:Suppressor Factors, Immunologic / Q000378:metabolism*; D014397:Tuberculosis, Pulmonary / Q000276:immunology / Q000378:metabolism*
D013491:Suppressor Factors, Immunologic