Immune Regulation in Toxoplasmosis and Other Opportunistic Infections

Sher, A.

Abstract

The overall aim of this project is to analyze the immune response to Toxoplasma gondii and other opportunistic infections 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. Demonstration of a superantigen activity in Toxoplasma gondii. Tachyzoites were shown to possess molecule(s) which stimulate proliferation of and IFN-gamma synthesis by splenocytes from uninfected animals. This activity, which fulfills all of the major criteria of a superantigen, may help explain both the early induction of cell-mediated immunity by T. gondii and the genetics of susceptibility to disease. B. Role of IL-12 in innate resistance. The induction of IL-12 was shown to be critical for the early IFN-gamma-dependent resistance of mice to acute infection but less important or non-essential for the prevention of disease reactivation. C. Studies on mechanisms of monokine induction by T. gondii. The triggering of the monokines TNF-alpha and IL-12 by T. gondii was shown to be independent of macrophage Lps receptors but to involve a similar signal transduction pathway. T. gondii was shown to be capable of stimulating HIV replication in virally infected human monocytes or macrophages from transgenic mice containing integrated provirus.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute of Allergy and Infectious Diseases (NIAID)
• Type: Intramural Research (Z01)
• Project #: 1Z01AI000579-05
• Application #: 3746588
• Support Year: 5
• Fiscal Year: 1994

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