Toxoplasma Gondii Bradyzoites Elicit Transcriptional Changes in Host Cells to Prevent IFNγ-Mediated Cell Death

2019 ◽  
Author(s):  
Simona Seizova ◽  
Alexandra L Garnham ◽  
Michael J Coffey ◽  
Lachlan W Whitehead ◽  
Kelly L Rogers ◽  
...  
Keyword(s):  
Cell Death ◽  
Toxoplasma Gondii ◽  
Host Cells ◽  
Transcriptional Changes

scholarly journals Toxoplasma gondiibradyzoites induce transcriptional changes to host cells and prevent IFNγ-mediated cell death

2019 ◽  
Author(s):  
Simona Seizova ◽  
Alexandra L Garnham ◽  
Michael J Coffey ◽  
Lachlan W Whitehead ◽  
Kelly L Rogers ◽  
...  
Keyword(s):  
Cell Death ◽  
Acute Stage ◽  
Effector Proteins ◽  
Host Cells ◽  
Host Manipulation ◽  
Parasite Protein ◽  
Congenital Birth Defects ◽  
Transcriptional Changes ◽  
Disease Reactivation ◽  
Transcriptional Landscape

SummaryToxoplasma gondii, the causative agent of toxoplasmosis, lies dormant for life and is a reservoir for disease reactivation, causing blindness, encephalitis and congenital birth defects. Acute-stage tachyzoites extensively manipulate their host cell by exporting a repertoire of proteins across the parasitophorous vacuolar membrane (PVM). This interferes with the hosts transcriptional program, allowing for persistence during immune attack. It is unknown how bradyzoites persist and what role host manipulation plays in latency. Here we show that bradyzoite-containing host cells have a unique transcriptional landscape when compared to tachyzoite infection. We demonstrate that many of these changes are dependent parasite protein export. Furthermore, we show that bradyzoite effector proteins protect host cell’s from IFNγ-mediated cell death, thus highlighting the functional importance of host manipulation. Together, our work provides the first understanding of howToxoplasmasets up latency to persist in its host.

Transcriptional modification of host cells harboring Toxoplasma gondii bradyzoites prevents IFN gamma-mediated cell death

2021 ◽  
Author(s):  
Simona Seizova ◽  
Ushma Ruparel ◽  
Alexandra L. Garnham ◽  
Stefanie M. Bader ◽  
Alessandro D. Uboldi ◽  
...  
Keyword(s):  
Cell Death ◽  
Toxoplasma Gondii ◽  
Host Cells ◽  
Ifn Gamma

Programmed Cell Death 5 from Toxoplasma gondii: A secreted molecule that exerts a pro-apoptotic effect on host cells

2008 ◽  
Vol 159 (2) ◽  
pp. 112-120 ◽  
Author(s):  
Hiroshi Bannai ◽  
Yoshifumi Nishikawa ◽  
Tomohide Matsuo ◽  
Osamu Kawase ◽  
Junichi Watanabe ◽  
...  
Keyword(s):  
Cell Death ◽  
Toxoplasma Gondii ◽  
Programmed Cell Death ◽  
Host Cells ◽  
Apoptotic Effect ◽  
Programmed Cell Death 5

Toxoplasma gondii Parasites Take Control within Host Cells

2012 ◽  
Vol 7 (8) ◽  
pp. 360-365
Author(s):  
Eric Y. Denkers ◽  
Barbara A. Butcher
Keyword(s):  
Toxoplasma Gondii ◽  
Host Cells

scholarly journals Pathogen induced subversion of NAD+ metabolism mediating host cell death: a target for development of chemotherapeutics

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Ayushi Chaurasiya ◽  
Swati Garg ◽  
Ashish Khanna ◽  
Chintam Narayana ◽  
Ved Prakash Dwivedi ◽  
...  
Keyword(s):  
Cell Death ◽  
Host Cell ◽  
Nicotinamide Adenine Dinucleotide ◽  
Malaria Parasite ◽  
Host Cells ◽  
Nicotinamide Adenine ◽  
Targeted Therapeutics ◽  
Nad Metabolism ◽  
Host Cell Death ◽  
Nanomolar Range

AbstractHijacking of host metabolic status by a pathogen for its regulated dissemination from the host is prerequisite for the propagation of infection. M. tuberculosis secretes an NAD+-glycohydrolase, TNT, to induce host necroptosis by hydrolyzing Nicotinamide adenine dinucleotide (NAD+). Herein, we expressed TNT in macrophages and erythrocytes; the host cells for M. tuberculosis and the malaria parasite respectively, and found that it reduced the NAD+ levels and thereby induced necroptosis and eryptosis resulting in premature dissemination of pathogen. Targeting TNT in M. tuberculosis or induced eryptosis in malaria parasite interferes with pathogen dissemination and reduction in the propagation of infection. Building upon our discovery that inhibition of pathogen-mediated host NAD+ modulation is a way forward for regulation of infection, we synthesized and screened some novel compounds that showed inhibition of NAD+-glycohydrolase activity and pathogen infection in the nanomolar range. Overall this study highlights the fundamental importance of pathogen-mediated modulation of host NAD+ homeostasis for its infection propagation and novel inhibitors as leads for host-targeted therapeutics.

scholarly journals Cell Death Signaling Pathway Induced by Cholix Toxin, a Cytotoxin and eEF2 ADP-Ribosyltransferase Produced by Vibrio cholerae

Toxins ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 12
Author(s):  
Kohei Ogura ◽  
Kinnosuke Yahiro ◽  
Joel Moss
Keyword(s):  
Cell Death ◽  
Protein Kinase ◽  
Vibrio Cholerae ◽  
Elongation Factor ◽  
Host Cells ◽  
Mitogen Activated Protein Kinase ◽  
Pseudomonas Exotoxin A ◽  
Tnf Α ◽  
Induced Apoptosis ◽  
Adp Ribosyltransferase

Pathogenic microorganisms produce various virulence factors, e.g., enzymes, cytotoxins, effectors, which trigger development of pathologies in infectious diseases. Cholera toxin (CT) produced by O1 and O139 serotypes of Vibrio cholerae (V. cholerae) is a major cytotoxin causing severe diarrhea. Cholix cytotoxin (Cholix) was identified as a novel eukaryotic elongation factor 2 (eEF2) adenosine-diphosphate (ADP)-ribosyltransferase produced mainly in non-O1/non-O139 V. cholerae. The function and role of Cholix in infectious disease caused by V. cholerae remain unknown. The crystal structure of Cholix is similar to Pseudomonas exotoxin A (PEA) which is composed of an N-terminal receptor-recognition domain and a C-terminal ADP-ribosyltransferase domain. The endocytosed Cholix catalyzes ADP-ribosylation of eEF2 in host cells and inhibits protein synthesis, resulting in cell death. In a mouse model, Cholix caused lethality with severe liver damage. In this review, we describe the mechanism underlying Cholix-induced cytotoxicity. Cholix-induced apoptosis was regulated by mitogen-activated protein kinase (MAPK) and protein kinase C (PKC) signaling pathways, which dramatically enhanced tumor necrosis factor-α (TNF-α) production in human liver, as well as the amount of epithelial-like HepG2 cancer cells. In contrast, Cholix induced apoptosis in hepatocytes through a mitochondrial-dependent pathway, which was not stimulated by TNF-α. These findings suggest that sensitivity to Cholix depends on the target cell. A substantial amount of information on PEA is provided in order to compare/contrast this well-characterized mono-ADP-ribosyltransferase (mART) with Cholix.

scholarly journals Ferroptotic cell death triggered by conjugated linolenic acids is mediated by ACSL1

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Alexander Beatty ◽  
Tanu Singh ◽  
Yulia Y. Tyurina ◽  
Vladimir A. Tyurin ◽  
Svetlana Samovich ◽  
...  
Keyword(s):  
Cell Death ◽  
Therapeutic Potential ◽  
Neutral Lipids ◽  
Cell Types ◽  
Lipid Hydroperoxides ◽  
Conjugated Linolenic Acids ◽  
Cellular Lipids ◽  
Transcriptional Changes ◽  
Acyl Chains ◽  
Tumor Growth And Metastasis

AbstractFerroptosis is associated with lipid hydroperoxides generated by the oxidation of polyunsaturated acyl chains. Lipid hydroperoxides are reduced by glutathione peroxidase 4 (GPX4) and GPX4 inhibitors induce ferroptosis. However, the therapeutic potential of triggering ferroptosis in cancer cells with polyunsaturated fatty acids is unknown. Here, we identify conjugated linoleates including α-eleostearic acid (αESA) as ferroptosis inducers. αESA does not alter GPX4 activity but is incorporated into cellular lipids and promotes lipid peroxidation and cell death in diverse cancer cell types. αESA-triggered death is mediated by acyl-CoA synthetase long-chain isoform 1, which promotes αESA incorporation into neutral lipids including triacylglycerols. Interfering with triacylglycerol biosynthesis suppresses ferroptosis triggered by αESA but not by GPX4 inhibition. Oral administration of tung oil, naturally rich in αESA, to mice limits tumor growth and metastasis with transcriptional changes consistent with ferroptosis. Overall, these findings illuminate a potential approach to ferroptosis, complementary to GPX4 inhibition.

scholarly journals Loss of a conserved MAPK causes catastrophic failure in assembly of a specialized cilium-like structure in Toxoplasma gondii

2020 ◽  
Vol 31 (9) ◽  
pp. 881-888 ◽  
Author(s):  
William J. O’Shaughnessy ◽  
Xiaoyu Hu ◽  
Tsebaot Beraki ◽  
Matthew McDougal ◽  
Michael L. Reese
Keyword(s):  
Toxoplasma Gondii ◽  
Host Cells ◽  
Ultrastructural Changes ◽  
Catastrophic Failure ◽  
Replicative Cycle

Toxoplasma gondii that lacks the kinase ERK7 cannot invade or egress from their host cells, thereby blocking their replicative cycle. These defects are due to the loss of a specialized cilium-like structure called the conoid. Strikingly, the ultrastructural changes are specific to the conoid, and suggest an important role for ERK7 in its biogenesis.

scholarly journals Toxoplasma gondii actively remodels the microtubule network in host cells

2008 ◽  
Vol 10 (14-15) ◽  
pp. 1440-1449 ◽  
Author(s):  
Margaret E. Walker ◽  
Elizabeth E. Hjort ◽  
Sherri S. Smith ◽  
Abhishek Tripathi ◽  
Jessica E. Hornick ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Host Cells ◽  
Microtubule Network
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