title: Suppression of TLR2-induced IL-12, reactive oxygen species, and inducible nitric oxide synthase expression by Mycobacterium tuberculosis antigens expressed inside macrophages during the course of infection.
abstract: We report the enrichment of and immune responses mediated by genes expressed by Mycobacterium tuberculosis inside macrophages as a function of time. Results indicate that M. tuberculosis expresses different genes at different times postinfection. Genes expressed early (day 1) following infection enhance M. tuberculosis-mediated activation of dendritic cells (DCs), whereas genes expressed later (day 5) in the infection prevent DC activation. However, all genes downmodulated MHC class I and II expression on infected macrophages, thus compromising their ability to interact with Ag-specific T cells. Day-1 and -5 genes downmodulated proinflammatory cytokine production from DCs, thus impairing signal 3 during DC-T cell cognate interactions. Consequently, T cells activated by Ag-experienced DCs secreted low levels of IFN-gamma and IL-17 but maintained high IL-10 secretion, thus inducing suppressor responses. Further characterization revealed that day-1 and -5 genes increased TLR2-induced expression of suppressors of cytokine signaling 1 from DCs and downmodulated IL-12 expression. In addition, day-1 and -5 genes prevented the generation of reactive oxygen species in DCs. In contrast, although day-5 genes increased TLR2-mediated suppressors of cytokine signaling 1 expression in macrophages, day-1 genes downmodulated the expression of inducible NO synthase 2. Similar downregulation of immune responses was observed upon exogenous stimulation with day-1 or -5 Ags. Finally, day-1 and -5 genes promoted enhanced survival of M. tuberculosis inside DCs and macrophages. These results indicate that M. tuberculosis genes, expressed inside infected macrophages as a function of time, collectively suppress protective immune responses by using multiple and complementary mechanisms.
authors.affiliation: Immunology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi, India.
authors.forename: Deepti
authors.initials: D
authors.lastname: Gupta
authors.forename: Sachin
authors.initials: S
authors.lastname: Sharma
authors.forename: Jhalak
authors.initials: J
authors.lastname: Singhal
authors.forename: Akash T
authors.initials: AT
authors.lastname: Satsangi
authors.forename: Cecil
authors.initials: C
authors.lastname: Antony
authors.forename: Krishnamurthy
authors.initials: K
authors.lastname: Natarajan
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D018664:Interleukin-12 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D008264:Macrophages / Q000201:enzymology / Q000276:immunology* / Q000382:microbiology; D017737:Macrophages, Peritoneal / Q000201:enzymology / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008807:Mice, Inbred BALB C; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000276:immunology*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors / Q000502:physiology*; D014397:Tuberculosis, Pulmonary / Q000201:enzymology / Q000276:immunology / Q000473:pathology
chemical_list: D000942:Antigens, Bacterial; D017382:Reactive Oxygen Species; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D018664:Interleukin-12; D052247:Nitric Oxide Synthase Type II