Prolonged Toll-Like Receptor Signaling byMycobacterium tuberculosisand Its 19-Kilodalton Lipoprotein Inhibits Gamma Interferon-Induced Regulation of Selected Genes in Macrophages
Year: 2004
Type: article
Abstract: Infection of macrophages with Mycobacterium tuberculosis or exposure to M. tuberculosis 19-kDa lipoprotein for >16 h inhibits gamma interferon (IFN-gamma)-induced major histocompatibility complex class II (MHC-II) expression by a mechanism involving Toll-like receptors (TLRs). M. tuberculosis was found to inhibit murine macrophage MHC-II antigen (Ag) processing activity induced by IFN-gamma but not by interleukin-4 (IL-4), suggesting inhibition of IFN-gamma-induced gene regulation. We designed an approach to test the ability of M. tuberculosis-infected cells to respond to IFN-gamma. To model chronic infection with M. tuberculosis with accompanying prolonged TLR signaling, macrophages were infected with M. tuberculosis or incubated with M. tuberculosis 19-kDa lipoprotein for 24 h prior to the addition of IFN-gamma. Microarray gene expression studies were then used to determine whether prolonged TLR signaling by M. tuberculosis broadly inhibits IFN-gamma regulation of macrophage gene expression. Of 347 IFN-gamma-induced genes, M. tuberculosis and 19-kDa lipoprotein inhibited induction of 42 and 36%, respectively. Key genes or gene products were also examined by quantitative reverse transcription-PCR and flow cytometry, confirming and extending the results obtained by microarray studies. M. tuberculosis inhibited IFN-gamma induction of genes involved in MHC-II Ag processing, Ag presentation, and recruitment of T cells. These effects were largely dependent on myeloid differentiation factor 88, implying a role for TLRs. Thus, prolonged TLR signaling by M. tuberculosis inhibits certain macrophage responses to IFN-gamma, particularly those related to MHC-II Ag presentation. This inhibition may promote M. tuberculosis evasion of T-cell responses and persistence of infection in tuberculosis.
Source: Infection and Immunity
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: American Lung Association, Case Western Reserve University, National Institutes of Health, Center for AIDS Research, University of Washington, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases
Awards: Regulation of macrophages by Mycobacterium tuberculosis, TRAINING GRANT IN TUMOR IMMUNOLOGY, Class II MHC Transport and Function, Medical Scientist Training Program, G4847828429, M. tuberculosis Infection in the Lung, Heterogeneity of T-cells in M. tuberculosis Infection, TUBERCULOSIS PREVENTION RESEARCH UNIT, IMMUNOMODULATORY EFFECTS OF CPG DNA, CD8+ T CELLS AND MYCOPLASMA TUBERCULOSIS, Case Comprehensive Cancer Center Support Grant, Rustbelt Center for AIDS Research (Case/UHC-Pitt CFAR)
OpenAlex ID: W2025216349