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Toxoplasma gondii exploits the migratory properties of monocytes and dendritic cells to promote tissue dissemination. Recently, ten Hoeve et al. reported that the parasite effector protein GRA28 conspires with host chromatin modifiers to confer dendritic cell-like features that convert sessile macrophages into migratory cells that transport infection to distal organs.

Plasmacytoid dendritic cells (pDC) are major producers of IFN- α , an antiviral cytokine with immunomodulatory and anti-viral activity. IFN- α production in pDC is inhibited by IL-10. Toxoplasma gondii is a life-threatening opportunistic infection in HIV-infected individuals, with areas with high incidence of HIV also endemic for T. gondii. We investigated human pDC responses with virus and T. gondii co-infection. Using flow cytometry and fluorescence microscopy, we determined that T. gondii invaded but did not induce IFN- α or TNF- α in pDC. However, T. gondii inhibited both IFN- α and TNF- α produced in response to HSV and HIV, thus functionally inactivating pDC. Within the T. gondii-exposed pDC population, IFN- α production was inhibited only in cells infected by T. gondii, demonstrating the inhibition occurs in cis. T. gondii inhibited neither uptake of GFP-HSV nor localization of TLR-9 in CD71+ endosomes. Using imaging flow cytometry, we found that virus-induced nuclear translocation of IRF7 but not phosphorylation was abolished by the parasite, similar to what we observed with IL-10 treatment of pDC. Taken together, these data indicate that the block of the intracellular signaling cascade by T. gondii occurs downstream of TLR9 recruitment but upstream of IRF7 translocation. Obstruction of IRF7 nuclear translocation and inhibition of IFN- α were partially reversed by knocking out T. gondii-derived ROP16 kinase, known to directly phosphorylate STAT3, further mimicking IL-10 anti-inflammatory signaling. These findings describe a novel mechanism of inhibition of TLR signaling by T. gondii whereby the pathogen mimics IL-10 signaling and suggest potential negative consequences of HIV/T. gondii co-infection.

Cell-mediated immune responses are essential for host control of intracellular infections. Toxoplasma gondii is a protozoan parasite that infects multiple vertebrate species and invades multiple cell types. Upon initial encounter with the immune system, the parasite rapidly induces production of the type-1 promoting cytokine IL-12 most likely from a subpopulation of dendritic cells. NK and T cells are then activated and triggered to synthesize IFN-gamma, the major mediator of host resistance during the acute and chronic phases of infection. During the acute phase, a concomitant IL-10 response dampens the systemic type-1 cytokine production and prevents lethal immunopathology. Cytokine (IFN-gamma und TNF-alpha) rather than cytotoxicity-based effector functions are more critical for protective immunity both during the acute and chronic phases of T. gondii infection. Both hemopoietic and non-hemopoietic cellular elements act as IFN-gamma and TNF-dependent effectors of host resistance. Type II iNOS-derived nitric oxide (NO) is required mainly for hemopoietic cell-derived effector cell activity in the central nervous system (CNS) during the chronic phase of infection. Nevertheless, in both the acute and chronic stages, IFN-gamma-dependent but iNOS-independent mechanism(s) play a major function in parasite control and their identification remains an important challenge for this field.

Interleukin-12 plays a major role in immunity to intracellular pathogens by governing the development of IFNγ-dependent host resistance. Nevertheless, unregulated IL-12 synthesis can lead to immunopathology, an outcome prevented by the concurrent expression of interleukin-10. Dendritic cells (DC) are an important source of the initial IL-12 stimulated by microbial agents. Here, we show that, following systemic triggering, DC can no longer be restimulated to produce IL-12 in vivo while continuing to respond in vitro. When infected with Toxoplasma gondii during this refractory state, mice mount impaired acute IFNγ responses and, in the case of IL-10-deficient animals, are protected from cytokine-induced mortality. These findings demonstrate a previously unrecognized form of immunologic paralysis involving DC that can protect from infection-induced immunopathology.

The course of anemia and the erythropoietic response in the bone marrow, spleen, and blood were studied during Plasmodium chabaudi AS infection in resistant C57BL/6 (B6) and susceptible A J (A) mice. Infections in B6 mice were characterized by moderate levels of both parasitemia and anemia and survival. In contrast, A mice experienced high parasitemia, severe anemia, and high mortality rates. During the period of anemia, erythropoiesis, as measured by in vivo59Fe incorporation, was significantly more depressed in bone marrow and more increased in the spleen in resistant B6 mice. The increase in splenic 59Fe incorporation was a function of the size of the spleen. Bone marrow CFU-E were decreased to 50% of control in both strains, while splenic CFU-E were increased twofold greater in B6 mice compared to those in A mice. However, the absolute numbers of CFU-E per spleen in the two strains were not significantly different during peak parasitemia. Bone marrow BFU-E were transiently increased before peak parasitemia whereas splenic BFU-E peaked during peak parasitemia. A mice had significantly lower numbers of BFU-E per spleen on all days except at peak parasitemia. The frequency of blood-borne BFU-E and plasma erythropoietin titers was increased earlier and to a greater extent in A mice. These results suggest that an impaired amplification of late-stage splenic erythropoiesis may be an important determinant in the severity of anemia and lethality of infection with P. chabaudi AS in A mice. Moreover, these results demonstrate that the defective amplification of splenic erythropoiesis in A mice is neither caused by a defect in the mobilization of BFU-E from the bone marrow to the spleen nor caused by a defect in erythropoietin production.