Malaria parasite induces tryptophan-related immune suppression in mice

Parasitology ◽  
2007 ◽  
Vol 134 (7) ◽  
pp. 923-930 ◽  
Author(s):  
K. TETSUTANI ◽  
H. TO ◽  
M. TORII ◽  
H. HISAEDA ◽  
K. HIMENO
Keyword(s):  
Biological Significance ◽  
Plasmodium Yoelii ◽  
Tryptophan Depletion ◽  
Malaria Parasites ◽  
Host Immune Responses ◽  
Tryptophan Catabolism ◽  
Ifn Γ ◽  
Rate Limiting ◽  
Malaria Model

SUMMARYPlasmodium spp. cause the worst parasitic diseases in humans and evade host immunity in complicated ways. Activated catabolism of tryptophan in dendritic cells is thought to suppress immunity, which is mediated by an inducible rate-limiting enzyme of tryptophan catabolism, indoleamine 2,3 dioxygenase (IDO), via both tryptophan depletion and production of toxic metabolites. In various infections, including malaria, IDO is known to be activated but its biological significance is unclear; therefore, we investigated whether malaria parasites induce IDO to suppress host immune responses. We found that enzymatic activity of IDO was elevated systematically in our mouse malaria model, and was abolished by in vivo IDO inhibition with 1-methyl tryptophan. Experimental infection with Plasmodium yoelii showed that IDO inhibition slightly suppressed parasite density in association with enhanced proliferation and IFN-γ production by CD4+ T cells in response to malaria parasites. Our observations suggest that induction of IDO is one of the immune mechanisms of malaria parasites.

scholarly journals A cytomegaloviral protein reveals a dual role for STAT2 in IFN-γ signaling and antiviral responses

2005 ◽  
Vol 201 (10) ◽  
pp. 1543-1553 ◽  
Author(s):  
Albert Zimmermann ◽  
Mirko Trilling ◽  
Markus Wagner ◽  
Manuel Wilborn ◽  
Ivan Bubic ◽  
...  
Keyword(s):  
Biological Significance ◽  
Receptor Expression ◽  
Type I ◽  
Antiviral Responses ◽  
Type I Ifns ◽  
New Strategy ◽  
Infected Cells ◽  
Ifn Γ

A mouse cytomegalovirus (MCMV) gene conferring interferon (IFN) resistance was identified. This gene, M27, encodes a 79-kD protein that selectively binds and down-regulates for signal transducer and activator of transcription (STAT)-2, but it has no effect on STAT1 activation and signaling. The absence of pM27 conferred MCMV susceptibility to type I IFNs (α/β), but it had a much more dramatic effect on type II IFNs (γ) in vitro and in vivo. A comparative analysis of M27+ and M27− MCMV revealed that the antiviral efficiency of IFN-γ was partially dependent on the synergistic action of type I IFNs that required STAT2. Moreover, STAT2 was directly activated by IFN-γ. This effect required IFN receptor expression and was independent of type I IFNs. IFN-γ induced increasing levels of tyrosine-phosphorylated STAT2 in M27− MCMV-infected cells that were essential for the antiviral potency of IFN-γ. pM27 represents a new strategy for simultaneous evasions from types I and II IFNs, and it documents an unknown biological significance for STAT2 in antiviral IFN-γ responses.

scholarly journals Nuclear lamin stiffness is a barrier to 3D migration, but softness can limit survival

2014 ◽  
Vol 204 (5) ◽  
pp. 669-682 ◽  
Author(s):  
Takamasa Harada ◽  
Joe Swift ◽  
Jerome Irianto ◽  
Jae-Won Shin ◽  
Kyle R. Spinler ◽  
...  
Keyword(s):  
Cell Sorting ◽  
Activation Barrier ◽  
Biological Significance ◽  
Cell Types ◽  
Elastic Stiffness ◽  
Lamin A ◽  
Net Migration ◽  
Nuclear Lamin ◽  
Rate Limiting

Cell migration through solid tissue often involves large contortions of the nucleus, but biological significance is largely unclear. The nucleoskeletal protein lamin-A varies both within and between cell types and was shown here to contribute to cell sorting and survival in migration through constraining micropores. Lamin-A proved rate-limiting in 3D migration of diverse human cells that ranged from glioma and adenocarcinoma lines to primary mesenchymal stem cells (MSCs). Stoichiometry of A- to B-type lamins established an activation barrier, with high lamin-A:B producing extruded nuclear shapes after migration. Because the juxtaposed A and B polymer assemblies respectively conferred viscous and elastic stiffness to the nucleus, subpopulations with different A:B levels sorted in 3D migration. However, net migration was also biphasic in lamin-A, as wild-type lamin-A levels protected against stress-induced death, whereas deep knockdown caused broad defects in stress resistance. In vivo xenografts proved consistent with A:B-based cell sorting, and intermediate A:B-enhanced tumor growth. Lamins thus impede 3D migration but also promote survival against migration-induced stresses.

scholarly journals The Gene for Aromatase, a Rate-Limiting Enzyme for Local Estrogen Biosynthesis, Is a Downstream Target Gene of Runx2 in Skeletal Tissues

2010 ◽  
Vol 30 (10) ◽  
pp. 2365-2375 ◽  
Author(s):  
Jae-Hwan Jeong ◽  
Youn-Kwan Jung ◽  
Hyo-Jin Kim ◽  
Jung-Sook Jin ◽  
Hyun-Nam Kim ◽  
...  
Keyword(s):  
Cultured Cells ◽  
Steroid Hormone ◽  
Biological Significance ◽  
Bone Homeostasis ◽  
Mineral Density ◽  
Aromatase Gene ◽  
Estrogen Biosynthesis ◽  
Rate Limiting

ABSTRACT The essential osteoblast-related transcription factor Runx2 and the female steroid hormone estrogen are known to play pivotal roles in bone homeostasis; however, the functional interaction between Runx2- and estrogen-mediated signaling in skeletal tissues is minimally understood. Here we provide evidence that aromatase (CYP19), a rate-limiting enzyme responsible for estrogen biosynthesis in mammals, is transcriptionally regulated by Runx2. Consistent with the presence of multiple Runx2 binding sites, the binding of Runx2 to the aromatase promoter was demonstrated in vitro and confirmed in vivo by chromatin immunoprecipitation assays. The bone-specific aromatase promoter is activated by Runx2, and endogenous aromatase gene expression is upregulated by Runx2 overexpression, establishing the aromatase gene as a target of Runx2. The biological significance of the Runx2 transcriptional control of the aromatase gene is reflected by the enhanced estrogen biosynthesis in response to Runx2 in cultured cells. Reduced in vivo expression of skeletal aromatase gene and low bone mineral density are evident in Runx2 mutant mice. Collectively, these findings uncover a novel link between Runx2-mediated osteoblastogenic processes and the osteoblast-mediated biosynthesis of estrogen as an osteoprotective steroid hormone.

scholarly journals Type I Interferons and Malaria: A Double-Edge Sword Against a Complex Parasitic Disease

2020 ◽  
Vol 10 ◽  
Author(s):  
Xiao He ◽  
Lu Xia ◽  
Keyla C. Tumas ◽  
Jian Wu ◽  
Xin-Zhuan Su
Keyword(s):  
T Cell Activation ◽  
Cell Activation ◽  
Adaptive Immune Response ◽  
Plasmodium Yoelii ◽  
Type I Interferons ◽  
Complex Life Cycle ◽  
Type I ◽  
Malaria Parasites ◽  
Cytokines And Chemokines

Type I interferons (IFN-Is) are important cytokines playing critical roles in various infections, autoimmune diseases, and cancer. Studies have also shown that IFN-Is exhibit ‘conflicting’ roles in malaria parasite infections. Malaria parasites have a complex life cycle with multiple developing stages in two hosts. Both the liver and blood stages of malaria parasites in a vertebrate host stimulate IFN-I responses. IFN-Is have been shown to inhibit liver and blood stage development, to suppress T cell activation and adaptive immune response, and to promote production of proinflammatory cytokines and chemokines in animal models. Different parasite species or strains trigger distinct IFN-I responses. For example, a Plasmodium yoelii strain can stimulate a strong IFN-I response during early infection, whereas its isogenetic strain does not. Host genetic background also greatly influences IFN-I production during malaria infections. Consequently, the effects of IFN-Is on parasitemia and disease symptoms are highly variable depending on the combination of parasite and host species or strains. Toll-like receptor (TLR) 7, TLR9, melanoma differentiation-associated protein 5 (MDA5), and cyclic GMP-AMP synthase (cGAS) coupled with stimulator of interferon genes (STING) are the major receptors for recognizing parasite nucleic acids (RNA/DNA) to trigger IFN-I responses. IFN-I levels in vivo are tightly regulated, and various novel molecules have been identified to regulate IFN-I responses during malaria infections. Here we review the major findings and progress in ligand recognition, signaling pathways, functions, and regulation of IFN-I responses during malaria infections.

scholarly journals A pan-cancer metabolic atlas of the tumor microenvironment

2020 ◽  
Author(s):  
Neha Rohatgi ◽  
Umesh Ghoshdastider ◽  
Probhonjon Baruah ◽  
Anders Jacobsen Skanderup
Keyword(s):  
Cancer Cells ◽  
Stromal Cells ◽  
Metabolic Genes ◽  
Metabolic States ◽  
Tryptophan Catabolism ◽  
Tumor Types ◽  
Rate Limiting ◽  
Pan Cancer ◽  
The Warburg Effect

AbstractTumors are heterogeneous cellular environments with entwined metabolic dependencies. Here, we used a tumor transcriptome deconvolution approach to profile the metabolic states of cancer and non-cancer (stromal) cells in bulk tumors of 20 solid tumor types. We identified metabolic genes and processes recurrently altered in cancer cells across tumor types, including pan-cancer upregulation of deoxythymidine triphosphate (dTTP) production. In contrast, the tryptophan catabolism rate limiting enzymes, IDO1 and TDO2, were highly overexpressed in stroma, suggesting that kynurenine-mediated suppression of antitumor immunity is predominantly constrained by the stroma. Oxidative phosphorylation was unexpectedly the most upregulated metabolic process in cancer cells compared to both stromal cells and a large atlas of cancer cell lines, suggesting that the Warburg effect may be less pronounced in cancer cells in vivo. Overall, our analysis highlights fundamental differences in metabolic states of cancer and stromal cells inside tumors and establishes a pan-cancer resource to interrogate tumor metabolism.

scholarly journals Swift Development of Protective Effector Functions in Naive Cd8+ T Cells against Malaria Liver Stages

2001 ◽  
Vol 194 (2) ◽  
pp. 173-180 ◽  
Author(s):  
Gen-ichiro Sano ◽  
Julius C.R. Hafalla ◽  
Alexandre Morrot ◽  
Ryo Abe ◽  
Juan J. Lafaille ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Ex Vivo ◽  
Cell Receptor ◽  
Plasmodium Yoelii ◽  
Parasite Development ◽  
Effector Functions ◽  
Ifn Γ

We generated T cell receptor transgenic mice specific for the liver stages of the rodent malaria parasite Plasmodium yoelii and studied the early events in the development of in vivo effector functions in antigen-specific CD8+ T cells. Differently to activated/memory cells, naive CD8+ T cells are not capable of exerting antiparasitic activity unless previously primed by parasite immunization. While naive cells need to differentiate before achieving effector status, the time required for this process is very short. Indeed, interferon (IFN)-γ and perforin mRNA are detectable 24 h after immunization and IFN-γ secretion and cytotoxic activity are detected ex vivo 24 and 48 h after immunization, respectively. In contrast, the proliferation of CD8+ T cells begins after 24 h and an increase in the total number of antigen-specific cells is detected only after 48 h. Remarkably, a strong CD8+ T cell–mediated inhibition of parasite development is observed in mice challenged with viable parasites only 24 h after immunization with attenuated parasites. These results indicate that differentiation of naive CD8+ T cells does not begin only after extensive cell division, rather this process precedes or occurs simultaneously with proliferation.

scholarly journals Characterization of theIn VitroChlamydia pecorumResponse to Gamma Interferon

2018 ◽  
Vol 86 (4) ◽  
Author(s):  
M. Mominul Islam ◽  
Martina Jelocnik ◽  
Wilhelmina M. Huston ◽  
Peter Timms ◽  
Adam Polkinghorne
Keyword(s):  
Immune Response ◽  
Epithelial Cells ◽  
Host Cell ◽  
Anthranilic Acid ◽  
Gamma Interferon ◽  
Tryptophan Depletion ◽  
Content Type ◽  
Natural Hosts ◽  
Ifn Γ

ABSTRACTChlamydia pecorumis an important intracellular bacterium that causes a range of diseases in animals, including a native Australian marsupial, the koala. In humans and animals, a gamma interferon (IFN-γ)-mediated immune response is important for the control of intracellular bacteria. The present study tested the hypotheses thatC. pecorumcan escape IFN-γ-mediated depletion of host cell tryptophan pools. In doing so, we demonstrated that, unlikeChlamydia trachomatis,C. pecorumis completely resistant to IFN-γ in human epithelial cells. While the growth ofC. pecorumwas inhibited in tryptophan-deficient medium, it could be restored by the addition of kynurenine, anthranilic acid, and indole, metabolites that could be exploited by the gene products of theC. pecorumtryptophan biosynthesis operon. We also found that expression oftrpgenes was detectable only whenC. pecorumwas grown in tryptophan-free medium, with gene repression occurring in response to the addition of kynurenine, anthranilic acid, and indole. When grown in bovine kidney epithelial cells, bovine IFN-γ also failed to restrict the growth ofC. pecorum, whileC. trachomatiswas inhibited, suggesting thatC. pecorumcould use the same mechanisms to evade the immune responsein vivoin its natural host. Highlighting the different mechanisms triggered by IFN-γ, however, both species failed to grow in murine McCoy cells treated with murine IFN-γ. This work confirms previous hypotheses about the potential survival ofC. pecorumafter IFN-γ-mediated host cell tryptophan depletion and raises questions about the immune pathways used by the natural hosts ofC. pecorumto control the widespread pathogen.

scholarly journals Highly Sensitive and Rapid Characterization of the Development of Synchronized Blood Stage Malaria Parasites Via Magneto-Optical Hemozoin Quantification

Biomolecules ◽  
2019 ◽  
Vol 9 (10) ◽  
pp. 579 ◽  
Author(s):  
Mária Pukáncsik ◽  
Petra Molnár ◽  
Ágnes Orbán ◽  
Ádám Butykai ◽  
Lívia Marton ◽  
...  
Keyword(s):  
Dynamic Equilibrium ◽  
Malaria Diagnosis ◽  
High Sensitivity ◽  
Plasmodium Yoelii ◽  
Blood Stage ◽  
Malaria Parasites ◽  
Parasite Infections ◽  
Parasitemia Level ◽  
Rapid Characterization

The rotating-crystal magneto-optical diagnostic (RMOD) technique was developed as a sensitive and rapid platform for malaria diagnosis. Herein, we report a detailed in vivo assessment of the synchronized Plasmodium vinckei lentum strain blood-stage infections by the RMOD method and comparing the results to the unsynchronized Plasmodium yoelii 17X-NL (non-lethal) infections. Furthermore, we assess the hemozoin production and clearance dynamics in chloroquine-treated compared to untreated self-resolving infections by RMOD. The findings of the study suggest that the RMOD signal is directly proportional to the hemozoin content and closely follows the actual parasitemia level. The lack of long-term accumulation of hemozoin in peripheral blood implies a dynamic equilibrium between the hemozoin production rate of the parasites and the immune system’s clearing mechanism. Using parasites with synchronous blood stage cycle, which resemble human malaria parasite infections with Plasmodium falciparum and Plasmodium vivax, we are demonstrating that the RMOD detects both hemozoin production and clearance rates with high sensitivity and temporal resolution. Thus, RMOD technique offers a quantitative tool to follow the maturation of the malaria parasites even on sub-cycle timescales.

scholarly journals Dendritic Cells Induce Immunity and Long-Lasting Protection against Blood-Stage Malaria despite an In Vitro Parasite-Induced Maturation Defect

2004 ◽  
Vol 72 (9) ◽  
pp. 5331-5339 ◽  
Author(s):  
Dodie S. Pouniotis ◽  
Owen Proudfoot ◽  
Violeta Bogdanoska ◽  
Vasso Apostolopoulos ◽  
Theodora Fifis ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Plasmodium Yoelii ◽  
Blood Stage ◽  
Interleukin 4 ◽  
Ifn Γ ◽  
Maturation Defect ◽  
Blood Stage Malaria

ABSTRACT Dendritic cells (DC) suffer a maturation defect following interaction with erythrocytes infected with malaria parasites and become unable to induce protective malaria liver-stage immunity. Here we show that, by contrast, maturation-arrested DC in vitro are capable of the successful induction of antigen-specific gamma interferon (IFN-γ) and interleukin 4 (IL-4) T-cell responses, antibody responses, and potent protection against lethal blood-stage malaria challenge in vivo. Similar results were found with DC pulsed with intact parasitized Plasmodium yoelii or Plasmodium chabaudi erythrocytes. Cross-strain protection was also induced. High levels of protection (80 to 100%) against lethal challenge were evident from 10 days after a single immunization and maintained up to 120 days. Interestingly, correlation studies versus blood-stage protection at different time points suggest that the immune effector mechanisms associated with protection could change over time. Antibody-independent, T-cell- and IL-12-associated protection was observed early after immunization, followed by antibody and IL-4-associated, IFN-γ-independent protection in long-term studies. These results indicate that DC, even when clearly susceptible to parasite-induced maturation defect effects in vitro, can be central to the induction of protection against blood-stage malaria in vivo.

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