title: Prolonged toll-like receptor signaling by Mycobacterium tuberculosis and its 19-kilodalton lipoprotein inhibits gamma interferon-induced regulation of selected genes in macrophages.
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.
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH 44106-4943, USA.
authors.forename: Rish K
authors.initials: RK
authors.lastname: Pai
authors.forename: Meghan E
authors.initials: ME
authors.lastname: Pennini
authors.forename: Aaron A R
authors.initials: AA
authors.lastname: Tobian
authors.forename: David H
authors.initials: DH
authors.lastname: Canaday
authors.forename: W Henry
authors.initials: WH
authors.lastname: Boom
authors.forename: Clifford V
authors.initials: CV
authors.lastname: Harding
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000276:immunology / Q000502:physiology*; D005786:Gene Expression Regulation; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology*; D008074:Lipoproteins / Q000276:immunology / Q000494:pharmacology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000276:immunology / Q000472:pathogenicity / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction; D051193:Toll-Like Receptors
chemical_list: C087864:19 kDa antigen, Mycobacterium; D001426:Bacterial Proteins; D000949:Histocompatibility Antigens Class II; D008074:Lipoproteins; D008562:Membrane Glycoproteins; D011506:Proteins; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors; D007371:Interferon-gamma