Reduced expression of the inducible nitric oxide synthase after infection with Toxoplasma gondii facilitates parasite replication in activated murine macrophages

Lüder, Carsten G. K.; Algner, Michaela; Lang, Christine; Bleicher, Nadja; Groβ, Uwe

doi:10.1016/s0020-7519(03)00092-4

Cited by 105 publications

(98 citation statements)

References 43 publications

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“…Cells were infected 10:1 with T. gondii in the lower compartment and subsequently analyzed for SOCS-1 expression after 5 and 20 h (one of two experiments; mean of triplicate determinations Ϯ SD). IIGP1 were inhibited, confirming and extending earlier findings of different groups (8,11,12,32), which showed modulation of iNOS activity by various T. gondii strains. We consistently observed that the inhibitory potential varied between different experiments and was dependent on the capacity to infect host cells.…”

Section: Discussionsupporting

confidence: 90%

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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

The Journal of Immunology

101

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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.

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Section: Discussionsupporting

confidence: 90%

“…We consistently observed that the inhibitory potential varied between different experiments and was dependent on the capacity to infect host cells. Thus, the parasite to host ratio to obtain similar inhibition might be different for various strains, as also proposed by others (11).…”

Section: Discussionmentioning

confidence: 64%

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

The Journal of Immunology

101

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“…gondii blocks parasite degradation by reducing NO production in activated macrophages (5,6). T. gondii accomplishes this through multiple strategies, including downregulating transcription of the enzyme iNOS, which is required for NO production (32). T. gondii also suppresses NO production by limiting the availability of the substrate required for NO production, L-arginine (5,7,8).…”

Section: Fig 5 Expression Of Proinflammatory Cytokines Is Increased Imentioning

confidence: 99%

Z-DNA Binding Protein Mediates Host Control of Toxoplasma gondii Infection

2016

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Intrinsic to Toxoplasma gondii infection is the parasite-induced modulation of the host immune response, which ensures establishment of a chronic lifelong infection. This manipulation of the host immune response allows T. gondii to not only dampen the ability of the host to eliminate the parasite but also trigger parasite differentiation to the slow-growing, encysted bradyzoite form. We previously used RNA sequencing (RNA-seq) to profile the transcriptomes of mice and T. gondii during acute and chronic stages of infection. One of the most abundant host transcripts during acute and chronic infection was Z-DNA binding protein 1 (ZBP1). In this study, we determined that ZBP1 functions to control T. gondii growth. In activated macrophages isolated from ZBP1 deletion (ZBP1 ؊/؊ ) mice, T. gondii has an increased rate of replication and a decreased rate of degradation. We also identified a novel function for ZBP1 as a regulator of nitric oxide (NO) production in activated macrophages, even in the absence of T. gondii infection. Upon stimulation, T. gondii-infected ZBP1 ؊/؊ macrophages display increased proinflammatory cytokines compared to wild-type macrophages under the same conditions. These in vitro phenotypes were recapitulated in vivo, with ZBP1؊/؊ mice having increased susceptibility to oral challenge, higher cyst burdens during chronic infection, and elevated inflammatory cytokine responses. Taken together, these results highlight a role for ZBP1 in assisting host control of T. gondii infection.

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“…Luder et al (2001) showed that T. gondii down-regulates MHC class II gene expression and antigen presentation by murine macrophages via interference with nuclear translocation of STAT1alpha. The same group has also demonstrated that T. gondii infection of macrophages results in reduced expression of inducible nitric oxide synthase and facilitates replication in activated macrophages (Luder et al 2003a), and that infection in neural antigen-presenting cells inhibits MHC class II expression by down-regulating the class II transactivator CIITA (Luder et al 2003b). Other investigators found that T. gondii inhibits host cell apoptosis by inducing the activation of the transcription factor NFkappaB, which in turn is regulating the expression of inhibitors of apoptosis in the host cell (reviewed by Sinai et al 2004).…”

Section: Host Cell Modulation and Parasite-host Cell Crosstalkmentioning

confidence: 93%

Neospora caninum and neosporosis — recent achievements in host and parasite cell biology and treatment

Hemphill

Gottstein

2006

Acta Parasitologica

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Neospora caninum is an apicomplexan parasite, which owes its importance to the fact that it represents the major infectious cause of bovine abortion worldwide. Its life cycle is comprised of three distinct stages: Tachyzoites, representing the proliferative and disease-causing stage, bradyzoites, representing a slowly replicating, tissue cyst-forming stage, and sporozoites, which represent the end product of a sexual process taking place within the intestinal tissue of the final canine host. Tachyzoites are capable of infecting a large variety of host cells in vitro and in vivo, while bradyzoites have been found mainly within the central nervous system. In order to survive, proliferate, and proceed in its life cycle, N. caninum has evolved some amazing features. First, the parasite profits immensely from its ability to interact with, and invade, a large number of host cell types. Secondly, N. caninum exploits its capability to respond to alterations in living conditions by converting into another stage (tachyzoite-to-bradyzoite or vice versa). Thirdly, this parasite has evolved mechanisms that modulate its host cells according to its own requirements, and these must, especially in the case of the bradyzoite stage, involve mechanisms that ensure long term survival of not only the parasite but also of the host cell. These three key events (host cell invasion -stage conversion -host cell modulation) represent potential targets for intervention. In order to elucidate the molecular and cellular bases of these important features of N. caninum, cell culture-based approaches and laboratory animal models are extensively exploited. In this review, we will summarize the present knowledge and achievements related to host cell and parasite cell biology.

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Reduced expression of the inducible nitric oxide synthase after infection with Toxoplasma gondii facilitates parasite replication in activated murine macrophages

Cited by 105 publications

References 43 publications

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

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

Z-DNA Binding Protein Mediates Host Control of Toxoplasma gondii Infection

Neospora caninum and neosporosis — recent achievements in host and parasite cell biology and treatment

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