title: Secreted Toxoplasma gondii molecules interfere with expression of MHC-II in interferon gamma-activated macrophages.
abstract: The obligate intracellular protozoan parasite Toxoplasma gondii interferes with major histocompatibility complex class II antigen presentation to dampen host CD4(+) T cell responses. While it is known that T. gondii inhibits major histocompatibility complex class II gene transcription and expression in infected host cells, the mechanism of this host manipulation is unknown. Here, we show that soluble parasite proteins inhibit IFNγ-induced expression of major histocompatibility complex class II on the surface of the infected cell in a dose-dependent response that was abolished by protease treatment. Subcellular fractionation of T. gondii tachyzoites revealed that the major histocompatibility complex class II inhibitory activity co-partitioned with rhoptries and/or dense granules. However, parasite mutants deleted for single rhoptries or dense granules genes (ROP1, 4/7, 14, 16 and 18 or GRA 2-9 and 12 knock-out strains) retained the ability to inhibit expression of major histocompatibility complex class II. In addition, excreted/secreted antigens released by extracellular tachyzoites displayed immunomodulatory activity characterized by an inhibition of major histocompatibility complex class II expression, and reduced expression and release of TNFα by macrophages. Tandem MS analysis of parasite excreted/secreted antigens generated a list of T. gondii secreted proteins that may participate in major histocompatibility complex class II inhibition and the modulation of host immune functions.
authors.affiliation: Institute of Parasitology, McGill University, Parasitology Building, 21,111 Lakeshore Road, Sainte-Anne-de-Bellevue, QC H9X 3V9, Canada; Centre for Host-Parasite Interaction, McGill University, Parasitology Building, 21,111 Lakeshore Road, Sainte-Anne-de-Bellevue, QC H9X 3V9, Canada.
authors.forename: Louis-Philippe
authors.initials: LP
authors.lastname: Leroux
authors.affiliation: Institute of Parasitology, McGill University, Parasitology Building, 21,111 Lakeshore Road, Sainte-Anne-de-Bellevue, QC H9X 3V9, Canada; Centre for Host-Parasite Interaction, McGill University, Parasitology Building, 21,111 Lakeshore Road, Sainte-Anne-de-Bellevue, QC H9X 3V9, Canada.
authors.forename: Dayal
authors.initials: D
authors.lastname: Dasanayake
authors.affiliation: Geisel School of Medicine at Dartmouth, Borwell Research Building, 1 Medical Center Drive, Lebanon, NH 03756, USA.
authors.forename: Leah M
authors.initials: LM
authors.lastname: Rommereim
authors.affiliation: Geisel School of Medicine at Dartmouth, Borwell Research Building, 1 Medical Center Drive, Lebanon, NH 03756, USA.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Fox
authors.affiliation: Geisel School of Medicine at Dartmouth, Borwell Research Building, 1 Medical Center Drive, Lebanon, NH 03756, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Bzik
authors.affiliation: Institute of Parasitology, McGill University, Parasitology Building, 21,111 Lakeshore Road, Sainte-Anne-de-Bellevue, QC H9X 3V9, Canada; Centre for Host-Parasite Interaction, McGill University, Parasitology Building, 21,111 Lakeshore Road, Sainte-Anne-de-Bellevue, QC H9X 3V9, Canada. Electronic address: armando.jardim@mail.mcgill.ca.
authors.forename: Armando
authors.initials: A
authors.lastname: Jardim
authors.affiliation: Institute of Parasitology, McGill University, Parasitology Building, 21,111 Lakeshore Road, Sainte-Anne-de-Bellevue, QC H9X 3V9, Canada; Carleton University Research Office, Dunton Tower, 1125 Colonel By Drive, Ottawa, ON K1S 5B6, Canada.
authors.forename: Florence S
authors.initials: FS
authors.lastname: Dzierszinski
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000235:genetics* / Q000276:immunology; D006790:Host-Parasite Interactions; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015800:Protozoan Proteins / Q000235:genetics / Q000276:immunology*; D014122:Toxoplasma / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D014123:Toxoplasmosis / Q000235:genetics / Q000276:immunology* / Q000469:parasitology
chemical_list: D000949:Histocompatibility Antigens Class II; D015800:Protozoan Proteins; D007371:Interferon-gamma
keywords: Antigen presentation; Excreted/secreted antigens; Immunomodulation; Major histocompatibility complex II; Secretory organelles; Toxoplasma gondii