Studies on Immune Regulation in Toxoplasmosis

Sher, A.

Abstract

The overall aim of this project is to analyze the immune response to Toxoplasma gondii in order to define which cellular immune components and parasite target antigens are involved in the control of infection and its breakdown in immunocompromised hosts. Progress was made this year in the following areas: A. In vivo analysis of macrophage functional markers and cytokine expression during reactivation of infection in brain tissue. Reactivation of T. gondii infection in mouse brain was shown to correlate with the disappearance of mRNA's encoding markers of macrophage activation and to be inducible by depletion of TNF-alpha. B. Function of NK cells as alternative effectors of IFN-gamma-dependent resistance. Studies on vaccine-induced resistance in CD8+ deficient mice indicated that NK cells can mediate immunity against T. gondii via the T independent production of IFN-gamma. C. Role of IL-12 in the induction by T. gondii of IFN-gamma from NK cells and the use of the cytokine in the stimulation of resistance in immunodeficient hosts. IL-12 was shown to play a crucial role in the induction of IFN-gamma synthesis in NK cells by T. gondii. Macrophage accessory cells were shown to be the source of the IL-12 induced by the parasite. When administered to immunodeficient mice, IL-12 was shown to induce partial resistance against T. gondii challenge.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute of Allergy and Infectious Diseases (NIAID)
• Type: Intramural Research (Z01)
• Project #: 1Z01AI000579-04
• Application #: 3768844
• Support Year: 4
• Fiscal Year: 1993

Institution

• Name: National Institute of Allergy and Infectious Diseases
• Country: United States

Publications

la Sala, Andrea; He, Jianping; Laricchia-Robbio, Leopoldo et al. (2009) Cholera toxin inhibits IL-12 production and CD8alpha+ dendritic cell differentiation by cAMP-mediated inhibition of IRF8 function. J Exp Med 206:1227-35

Goldszmid, Romina S; Coppens, Isabelle; Lev, Avital et al. (2009) Host ER-parasitophorous vacuole interaction provides a route of entry for antigen cross-presentation in Toxoplasma gondii-infected dendritic cells. J Exp Med 206:399-410

Plattner, Fabienne; Yarovinsky, Felix; Romero, Stephane et al. (2008) Toxoplasma profilin is essential for host cell invasion and TLR11-dependent induction of an interleukin-12 response. Cell Host Microbe 3:77-87

Feng, Carl G; Zheng, Lixin; Jankovic, Dragana et al. (2008) The immunity-related GTPase Irgm1 promotes the expansion of activated CD4+ T cell populations by preventing interferon-gamma-induced cell death. Nat Immunol 9:1279-87

Goldszmid, Romina S; Bafica, Andre; Jankovic, Dragana et al. (2007) TAP-1 indirectly regulates CD4+ T cell priming in Toxoplasma gondii infection by controlling NK cell IFN-gamma production. J Exp Med 204:2591-602

Trinchieri, Giorgio; Sher, Alan (2007) Cooperation of Toll-like receptor signals in innate immune defence. Nat Rev Immunol 7:179-90

Jankovic, Dragana; Kullberg, Marika C; Feng, Carl G et al. (2007) Conventional T-bet(+)Foxp3(-) Th1 cells are the major source of host-protective regulatory IL-10 during intracellular protozoan infection. J Exp Med 204:273-83

Amsen, Derk; Antov, Andrey; Jankovic, Dragana et al. (2007) Direct regulation of Gata3 expression determines the T helper differentiation potential of Notch. Immunity 27:89-99

Bertholet, Sylvie; Goldszmid, Romina; Morrot, Alexandre et al. (2006) Leishmania antigens are presented to CD8+ T cells by a transporter associated with antigen processing-independent pathway in vitro and in vivo. J Immunol 177:3525-33

Collazo, Carmen M; Sher, Alan; Meierovics, Anda I et al. (2006) Myeloid differentiation factor-88 (MyD88) is essential for control of primary in vivo Francisella tularensis LVS infection, but not for control of intra-macrophage bacterial replication. Microbes Infect 8:779-90