Toxoplasma gondii down-regulates MHC class II gene expression and antigen presentation by murine macrophages via interference with nuclear translocation of STAT1α

Despite its noted ability to induce strong cellular immunity, and its known susceptibility to IFN-γ-dependent immune effector mechanisms, the protozoan Toxoplasma gondii is a highly successful parasite, able to replicate, disseminate, and either kill the host or, more commonly, establish resistant encysted life forms before the emergence of protective immune responses. We sought to understand how the parasite gains the advantage. Using transgenic clonal parasite lines engineered to express fluorescent markers in combination with dendritic cells (DC) grown from the bone marrow of wild-type mice or transgenic mice expressing fluorescent protein-tagged MHC class II molecules, we used flow cytometry and fluorescence microscopy to analyze the responses of infected DC to both invasion by the parasite and subsequent DC maturation signals. We found that T. gondii preferentially invades immature dendritic cells but fails to activate them in the process, and renders them resistant to subsequent activation by TLR ligands or the immune-system-intrinsic maturation signal CD40L. The functional consequences of T. gondii-mediated suppression of DC activation are manifested in a relative inability of infected immature DC to activate naive CD4+ Th lymphocytes, or to secrete cytokines, such IL-12 and TNF-α, that play important roles in innate and/or adaptive immunity. The findings reveal that T. gondii suppresses the ability of immature DC to participate in innate immunity and to induce adaptive immune responses. The ability of T. gondii to temporarily evade recognition could provide a selective advantage that permits dissemination and establishment before adaptive immune response initiation.

supporting

confidence: 88%

Functional Inactivation of Immature Dendritic Cells by the Intracellular Parasite Toxoplasma gondii

McKee

Dzierszinski

Boes

et al. 2004

“…In fact, it has been reported that resident sinus lining macrophages (F4/80 ϩ ) are only moderately responsive to IFN-␥ compared with peritoneal macrophages and that the oxidative competence of listeria-infected splenocytes is associated with infiltrating monocytes rather than with resident macrophages (40). Alternatively, L. monocytogenes could down-modulate IIGP expression in infected cells because it interferes with IFN-␥-induced signaling (41)(42)(43). Nevertheless, it is tempting to speculate that cells which initially interact with blood-borne pathogens, like IFN-␥-activated macrophages in the MZ or endothelial cells, contribute to the control of pathogen replication and dissemination via mechanism(s) governed by members of the 47-kDa GTPase family.…”

Section: Discussionmentioning

confidence: 79%

The IFN-Inducible Golgi- and Endoplasmic Reticulum- Associated 47-kDa GTPase IIGP Is Transiently Expressed During Listeriosis

Zerrahn¹,

Schaible²,

Brinkmann

et al. 2002

Members of the 47-kDa GTPase family are implicated in an IFN-γ-induced, as yet unclear, mechanism that confers innate resistance against infection with intracellular pathogens. Overt immunological parameters are apparently uncompromised in mice deficient for individual members and the prototype of this family, IGTP, localizes to the endoplasmic reticulum. This suggests that these GTPases are involved in intracellular defense. We analyzed the expression of the 47-kDa GTPase cognate, IIGP, in splenic sections from mice infected with the intracellular pathogen Listeria monocytogenes by immunohistochemistry. An early transient IIGP induction was observed revealing the IFN-γ responsiveness of cellular subcompartments within the spleen in early listeriosis. Marginal metallophilic macrophages and endothelial cells within the red and white pulp strongly expressed IIGP, while other splenocytes remained negative. In vitro analyses show that both type I and type II IFNs are prime stimuli for IIGP induction in various cells, including L. monocytogenes-infected or LPS-stimulated macrophages, endothelial cells, and activated T cells. Contrary to the subcellular localization of IGTP, IIGP was predominantly associated with the Golgi apparatus and also localizes to the endoplasmic reticulum. We conclude that IIGP exerts a distinct role in IFN-induced intracellular membrane trafficking or processing.

“…This contrasts with the findings of Luder et al (10), who did not observe inhibition of phosphorylation. However, they used much higher doses of IFN-␥ and a lower parasite to host ratio.…”

Section: Discussionmentioning

confidence: 99%

Induction of Suppressor of Cytokine Signaling-1 byToxoplasma gondiiContributes to Immune Evasion in Macrophages by Blocking IFN-γ Signaling

Zimmermann

Murray

Heeg

et al. 2006

101

Toxoplasma gondii is an intracellular parasite that survives and multiplies in professional phagocytes such as macrophages. Therefore, T. gondii has to cope with the panel of antimicrobial host immune mechanisms, among which IFN-γ plays a crucial role. We report in this study that in vitro infection of murine macrophages with viable, but not with inactivated, parasites results in inhibition of IFN-γ signaling within the infected cells. Thus, infection of RAW264.7 macrophages with tachyzoites inhibited IFN-γ-induced STAT-1 tyrosine phosphorylation, mRNA expression of target genes, and secretion of NO. These effects were dependent on direct contact of the host cells with living parasites and were not due to secreted intermediates. In parallel, we report the induction of suppressor of cytokine signaling-1 (SOCS-1), which is a known feedback inhibitor of IFN-γ receptor signaling. SOCS-1 was induced directly by viable parasites. SOCS overexpression in macrophages did not affect tachyzoite proliferation per se, yet abolished the inhibitory effects of IFN-γ on parasite replication. The inhibitory effects of T. gondii on IFN-γ were diminished in macrophages from SOCS-1−/− mice. The results suggest that induction of SOCS proteins within phagocytes due to infection with T. gondii contributes to the parasite’s immune evasion strategies.