TLR-Dependent Induction of IFN-β Mediates Host Defense against <i>Trypanosoma cruzi</i>

Koga, Ritsuko; Hamano, Shinjiro; Kuwata, Hirotaka; Atarashi, Koji; Ogawa, Masahiro; Hisaeda, Hajime; Yamamoto, Masahiro; Akira, Shizuo; Himeno, Kunisuke; Matsumoto, Makoto; Takeda, Kiyoshi

doi:10.4049/jimmunol.177.10.7059

Cited by 88 publications

(104 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This result prompted the conclusion that the death or killing of T. cruzi by host cells was required to release agonists of TLR9 (34). Macrophages and DC appear to have a more potent PRR-dependent responses to T. cruzi (35), related perhaps to their higher expression and diversity of PRR and to their enhanced phagocytic and cytotoxic activity relative to other host cells. The ability of T. cruzi to invade many different host cells other than these phagocytic cells, as well as to quickly exit phagolysosomes, might also assist in avoiding early immune system recognition.…”

Section: Discussionmentioning

confidence: 99%

Insufficient TLR Activation Contributes to the Slow Development of CD8+ T Cell Responses in Trypanosoma cruzi Infection

Padilla

Simpson

Tarleton

2009

The Journal of Immunology

View full text Add to dashboard Cite

During experimental infection with Trypanosoma cruzi, mice develop a strong CD8+ T cell response focused mainly on a few immunodominant peptides encoded in trans-sialidase family genes. Despite the potency of this response, the initial emergence and peak of parasite-specific CD8+ T cells has been noted to be relatively slow. In this study, we further document this delayed onset of T cell responses to T. cruzi as measured by the increase in frequency of parasite-specific T cells, the effector function of these cells, T cell proliferation in general, and the recruitment of cells into the draining lymph nodes. This delay does not appear to be the result of general immunosuppressive effects of the infection, a limitation in parasite numbers, or parasite trafficking to lymph nodes or to the specific epitope. Increasing the initial infecting dose or the density of parasite epitopes on APCs can modestly speed the generation of anti-T. cruzi T cell responses. Given these characteristics of the response, we propose that T. cruzi is a stealth invader, largely avoiding recognition by components of the innate immune system until the infection is well established. This conclusion is supported by the ability to accelerate the induction of T cell responses to T. cruzi by administration of ligands for TLR2 and TLR9 at the time of infection. These studies highlight a previously unappreciated mechanism of immune evasion, the surreptitious establishment of infection, by the protozoan T. cruzi.

show abstract

Section: Discussionmentioning

confidence: 99%

Insufficient TLR Activation Contributes to the Slow Development of CD8+ T Cell Responses in Trypanosoma cruzi Infection

Padilla

Simpson

Tarleton

2009

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Despite observations that T. cruzi elicits a prominent type I IFN response early in infection (10,13,52), it is presently unclear if type I IFNs play a role in innate resistance to T. cruzi (12,22,51). The goal of the present study was to determine whether type I IFN-dependent signaling plays a role in innate host resistance to T. cruzi infection.…”

mentioning

confidence: 97%

“…Cytokines produced during acute infection, such as interleukin-12 (IL-12), tumor necrosis factor alpha (TNF-␣), and gamma interferon (IFN-␥), as well as nitric oxide, play critical roles in controlling T. cruzi infection in the acute stage of infection (33). In addition, T. cruzi triggers a TLR-independent type I IFN response (9) in isolated cells and in murine models of acute infection (10,12,21,22,51,52).…”

mentioning

confidence: 99%

Type I Interferons Increase Host Susceptibility to Trypanosoma cruzi Infection

et al. 2011

View full text Add to dashboard Cite

Trypanosoma cruzi, the protozoan parasite that causes human Chagas' disease, induces a type I interferon (IFN) (IFN-␣/␤) response during acute experimental infection in mice and in isolated primary cell types. To examine the potential impact of the type I IFN response in shaping outcomes in experimental T. cruzi infection, groups of wild-type (WT) and type I IFN receptor-deficient (IFNAR ؊/؊ ) 129sv/ev mice were infected with two different T. cruzi strains under lethal and sublethal conditions and several parameters were measured during the acute stage of infection. The results demonstrate that type I IFNs are not required for early host protection against T. cruzi. In contrast, under conditions of lethal T. cruzi challenge, WT mice succumbed to infection whereas IFNAR ؊/؊ mice were ultimately able to control parasite growth and survive. T. cruzi clearance in and survival of IFNAR ؊/؊ mice were accompanied by higher levels of IFN-␥ production by isolated splenocytes in response to parasite antigen. The suppression of IFN-␥ in splenocytes from WT mice was independent of IL-10 levels. While the impact of type I IFNs on the production of IFN-␥ and other cytokines/chemokines remains to be fully determined in the context of T. cruzi infection, our data suggest that, under conditions of high parasite burden, type I IFNs negatively impact IFN-␥ production, initiating a detrimental cycle that contributes to the ultimate failure to control infection. These findings are consistent with a growing theme in the microbial pathogenesis field in which type I IFNs can be detrimental to the host in a variety of nonviral pathogen infection models.

show abstract

“…These data implicate Irgm3 in restricting Toxoplasma gondii (22,23) and C. trachomatis (16) survival; Irgm1 in restricting Mycobacterium tuberculosis (24), Trypanosoma cruzi (25), and Toxoplasma gondii (22); Irga6 in restricting T. gondii (21); and Irgd in restricting T. cruzi (26). Because IRG proteins often localize to pathogen-containing vacuoles as the pathogen enters the host cell and remain with the vacuole as it is processed (20,22), it has been suggested that the proteins regulate processing of pathogen-containing vacuoles, thereby governing growth and survival of the pathogen.…”

mentioning

confidence: 98%

Impaired Macrophage Function Underscores Susceptibility to Salmonella in Mice Lacking Irgm1 (LRG-47)

Henry

Daniell

Indaram

et al. 2007

The Journal of Immunology

View full text Add to dashboard Cite

IRG proteins, or immunity-related GTPases (also known as p47 GTPases), are a group of IFN-regulated proteins that are highly expressed in response to infection. The proteins localize to intracellular membranes including vacuoles that contain pathogens in infected macrophages and other host cells. Current data indicate that the IRG protein Irgm1 (LRG-47) is critical for resistance to intracellular bacteria. This function is thought to be a consequence of regulating the survival of vacuolar bacteria in host cells. In the current work, the role of Irgm1 in controlling resistance to Salmonella typhimurium was explored to further define the mechanism through which the protein regulates host resistance. Irgm1-deficient mice displayed increased susceptibility to this bacterium that was reflected in increased bacterial loads in spleen and liver and decreased maturation of S. typhimurium granulomas. The mice also displayed an inability to concentrate macrophages at sites of bacterial deposition. In vitro, the ability of Irgm1-deficient macrophages to suppress intracellular growth of S. typhimurium was impaired. Furthermore, adhesion and motility of Irgm1-deficient macrophages after activation with IFN-γ was markedly decreased. Altered adhesion/motility of those cells was accompanied by changes in cell morphology, density of adhesion-associated proteins, and actin staining. Together, these data suggest that in addition to regulating the maturation of pathogen-containing vacuoles, Irgm1 plays a key role in regulating the adhesion and motility of activated macrophages.

show abstract

TLR-Dependent Induction of IFN-β Mediates Host Defense against Trypanosoma cruzi

Cited by 88 publications

References 48 publications

Insufficient TLR Activation Contributes to the Slow Development of CD8+ T Cell Responses in Trypanosoma cruzi Infection

Insufficient TLR Activation Contributes to the Slow Development of CD8+ T Cell Responses in Trypanosoma cruzi Infection

Type I Interferons Increase Host Susceptibility to Trypanosoma cruzi Infection

Impaired Macrophage Function Underscores Susceptibility to Salmonella in Mice Lacking Irgm1 (LRG-47)

Contact Info

Product

Resources

About