scholarly journals An extracellular redox signal triggers calcium release and impacts the asexual development of Toxoplasma gondii

2021 ◽  
Author(s):  
Eduardo Alves ◽  
Henry J. Benns ◽  
Lilian Magnus ◽  
Caia Dominicus ◽  
Tamás Dobai ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Calcium Release ◽  
Catalytic Domain ◽  
Parasitophorous Vacuole ◽  
Human Fibroblasts ◽  
Calcium Dependent ◽  
Intracellular Ca ◽  
The Rich ◽  
Sense And Respond ◽  
The Impact

AbstractThe ability of an organism to sense and respond to environmental redox fluctuations relies on a signaling network that is incompletely understood in the apicomplexan parasite Toxoplasma gondii. The impact of changes in redox upon the development of this intracellular parasite is not known. Here, we provide a revised collection of 49 genes containing domains related to canonical antioxidant groups, with their encoded proteins widely dispersed throughout different cellular compartments. We demonstrate that addition of exogenous H2O2 to human fibroblasts infected with T. gondii triggers a Ca2+ flux in the cytosol of intracellular parasites that can induce egress. In line with existing models, egress triggered by exogenous H2O2 is reliant upon both Calcium-Dependent Protein Kinase 3 and diacylglycerol kinases. Finally, we show that the overexpression of the active catalytic domain of glutaredoxin in the parasitophorous vacuole severely impacts parasite replication. These data shed light on the rich redox network that exists in T. gondii, evidencing a link between extracellular redox and intracellular Ca2+ signaling that can culminate in parasite egress. Our findings also indicate that the redox potential of the intracellular environment contributes to normal parasite growth. Combined, our findings highlight the important role of redox as an unexplored regulator of parasite biology.

scholarly journals An Extracellular Redox Signal Triggers Calcium Release and Impacts the Asexual Development of Toxoplasma gondii

2021 ◽  
Vol 11 ◽  
Author(s):  
Eduardo Alves ◽  
Henry J. Benns ◽  
Lilian Magnus ◽  
Caia Dominicus ◽  
Tamás Dobai ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Calcium Release ◽  
Parasitophorous Vacuole ◽  
Human Fibroblasts ◽  
Calcium Dependent ◽  
Intracellular Parasites ◽  
Intracellular Ca ◽  
The Rich ◽  
Sense And Respond ◽  
The Impact

The ability of an organism to sense and respond to environmental redox fluctuations relies on a signaling network that is incompletely understood in apicomplexan parasites such as Toxoplasma gondii. The impact of changes in redox upon the development of this intracellular parasite is not known. Here, we provide a revised collection of 58 genes containing domains related to canonical antioxidant function, with their encoded proteins widely dispersed throughout different cellular compartments. We demonstrate that addition of exogenous H2O2 to human fibroblasts infected with T. gondii triggers a Ca2+ flux in the cytosol of intracellular parasites that can induce egress. In line with existing models, egress triggered by exogenous H2O2 is reliant upon both Calcium-Dependent Protein Kinase 3 and diacylglycerol kinases. Finally, we show that the overexpression a glutaredoxin-roGFP2 redox sensor fusion protein in the parasitophorous vacuole severely impacts parasite replication. These data highlight the rich redox network that exists in T. gondii, evidencing a link between extracellular redox and intracellular Ca2+ signaling that can culminate in parasite egress. Our findings also indicate that the redox potential of the intracellular environment contributes to normal parasite growth. Combined, our findings highlight the important role of redox as an unexplored regulator of parasite biology.

A SIMPLE MODEL FOR INTERACTION OF VOLTAGE AND CALCIUM DYNAMICS IN VIRTUAL VENTRICULAR TISSUE

2003 ◽  
Vol 13 (12) ◽  
pp. 3873-3886
Author(s):  
O. V. ASLANIDI ◽  
A. V. HOLDEN
Keyword(s):  
Intracellular Calcium ◽  
Calcium Release ◽  
Cell Model ◽  
Excitation Threshold ◽  
Calcium Dynamics ◽  
Variable Model ◽  
Ventricular Cell ◽  
Calcium Dependent ◽  
Intracellular Ca ◽  
A Site

A simple two-variable model is used to replace the formulation of calcium dynamics in the Luo–Rudy ventricular cell model. Virtual ventricular cell and tissue are developed and validated to reproduce restitution properties and calcium-dependent voltage patterns present in the original model. Basic interactions between the membrane potential and Ca 2+ dynamics in the virtual cell and a strand of the virtual tissue are studied. Intracellular calcium waves can be linked to both action potentials (APs) and delayed afterdepolarizations (DADs). An intracellular calcium wave propagating from the cell interior can induce an AP upon reaching the cell membrane. The voltage and the intracellular Ca 2+ patterns within the same cell can be highly desynchronized. In a one-dimensional strand of the virtual tissue calcium motion is driven by the AP propagation. However, calcium release can be induced upon certain conditions (e.g. Na + overload of the cells), which results in DADs propagating in the wake of AP. Such propagating DADs can reach the excitation threshold, generating a pair of extrasystolic APs. Collision of a propagating AP with a site of elevated intracellular Ca 2+ concentration does not affect the propagation under the normal conditions. Under Na + overload local elevation of the intracellular Ca 2+ leads to generation of an extrasystolic AP, which destroys the original propagating AP.

Besnoitia besnoiti and Toxoplasma gondii: two apicomplexan strategies to manipulate the host cell centrosome and Golgi apparatus

Parasitology ◽  
2014 ◽  
Vol 141 (11) ◽  
pp. 1436-1454 ◽  
Author(s):  
RITA CARDOSO ◽  
SOFIA NOLASCO ◽  
JOÃO GONÇALVES ◽  
HELDER C. CORTES ◽  
ALEXANDRE LEITÃO ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Golgi Apparatus ◽  
Host Cell ◽  
Parasitophorous Vacuole ◽  
Host Cells ◽  
Besnoitia Besnoiti ◽  
Microtubule Cytoskeleton ◽  
Cytoskeleton Organization ◽  
Evolutionary Paths ◽  
The Impact

SUMMARYBesnoitia besnoiti and Toxoplasma gondii are two closely related parasites that interact with the host cell microtubule cytoskeleton during host cell invasion. Here we studied the relationship between the ability of these parasites to invade and to recruit the host cell centrosome and the Golgi apparatus. We observed that T. gondii recruits the host cell centrosome towards the parasitophorous vacuole (PV), whereas B. besnoiti does not. Notably, both parasites recruit the host Golgi apparatus to the PV but its organization is affected in different ways. We also investigated the impact of depleting and over-expressing the host centrosomal protein TBCCD1, involved in centrosome positioning and Golgi apparatus integrity, on the ability of these parasites to invade and replicate. Toxoplasma gondii replication rate decreases in cells over-expressing TBCCD1 but not in TBCCD1-depleted cells; while for B. besnoiti no differences were found. However, B. besnoiti promotes a reorganization of the Golgi ribbon previously fragmented by TBCCD1 depletion. These results suggest that successful establishment of PVs in the host cell requires modulation of the Golgi apparatus which probably involves modifications in microtubule cytoskeleton organization and dynamics. These differences in how T. gondii and B. besnoiti interact with their host cells may indicate different evolutionary paths.

scholarly journals A Member of the Ferlin Calcium Sensor Family Is Essential for Toxoplasma gondii Rhoptry Secretion

mBio ◽  
2018 ◽  
Vol 9 (5) ◽  
Author(s):  
Bradley I. Coleman ◽  
Sudeshna Saha ◽  
Seiko Sato ◽  
Klemens Engelberg ◽  
David J. P. Ferguson ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Host Cell ◽  
Cell Invasion ◽  
Host Cells ◽  
Model Organisms ◽  
Host Cell Invasion ◽  
Content Type ◽  
Calcium Dependent ◽  
Calcium Sensing ◽  
Intracellular Ca

ABSTRACT Invasion of host cells by apicomplexan parasites such as Toxoplasma gondii is critical for their infectivity and pathogenesis. In Toxoplasma, secretion of essential egress, motility, and invasion-related proteins from microneme organelles is regulated by oscillations of intracellular Ca2+. Later stages of invasion are considered Ca2+ independent, including the secretion of proteins required for host cell entry and remodeling from the parasite’s rhoptries. We identified a family of three Toxoplasma proteins with homology to the ferlin family of double C2 domain-containing Ca2+ sensors. In humans and model organisms, such Ca2+ sensors orchestrate Ca2+-dependent exocytic membrane fusion with the plasma membrane. Here we focus on one ferlin that is conserved across the Apicomplexa, T. gondii FER2 (TgFER2). Unexpectedly, conditionally TgFER2-depleted parasites secreted their micronemes normally and were completely motile. However, these parasites were unable to invade host cells and were therefore not viable. Knockdown of TgFER2 prevented rhoptry secretion, and these parasites failed to form the moving junction at the parasite-host interface necessary for host cell invasion. Collectively, these data demonstrate the requirement of TgFER2 for rhoptry secretion in Toxoplasma tachyzoites and suggest a possible Ca2+ dependence of rhoptry secretion. These findings provide the first mechanistic insights into this critical yet poorly understood aspect of apicomplexan host cell invasion. IMPORTANCE Apicomplexan protozoan parasites, such as those causing malaria and toxoplasmosis, must invade the cells of their hosts in order to establish a pathogenic infection. Timely release of proteins from a series of apical organelles is required for invasion. Neither the vesicular fusion events that underlie secretion nor the observed reliance of the various processes on changes in intracellular calcium concentrations is completely understood. We identified a group of three proteins with strong homology to the calcium-sensing ferlin family, which are known to be involved in protein secretion in other organisms. Surprisingly, decreasing the amounts of one of these proteins (TgFER2) did not have any effect on the typically calcium-dependent steps in invasion. Instead, TgFER2 was essential for the release of proteins from organelles called rhoptries. These data provide a tantalizing first look at the mechanisms controlling the very poorly understood process of rhoptry secretion, which is essential for the parasite’s infection cycle.

scholarly journals NADPH oxidase-2 inhibition restores contractility and intracellular calcium handling and reduces arrhythmogenicity in dystrophic cardiomyopathy

2014 ◽  
Vol 307 (5) ◽  
pp. H710-H721 ◽  
Author(s):  
Daniel R. Gonzalez ◽  
Adriana V. Treuer ◽  
Guillaume Lamirault ◽  
Vera Mayo ◽  
Yenong Cao ◽  
...  
Keyword(s):  
Nadph Oxidase ◽  
Calcium Release ◽  
Calcium Handling ◽  
Mdx Mouse ◽  
No Production ◽  
Wild Type ◽  
Intracellular Ca ◽  
Dystrophic Cardiomyopathy ◽  
The Impact ◽  
Phospholamban Phosphorylation

Duchenne muscular dystrophy may affect cardiac muscle, producing a dystrophic cardiomyopathy in humans and the mdx mouse. We tested the hypothesis that oxidative stress participates in disrupting calcium handling and contractility in the mdx mouse with established cardiomyopathy. We found increased expression (fivefold) of the NADPH oxidase (NOX) 2 in the mdx hearts compared with wild type, along with increased superoxide production. Next, we tested the impact of NOX2 inhibition on contractility and calcium handling in isolated cardiomyocytes. Contractility was decreased in mdx myocytes compared with wild type, and this was restored toward normal by pretreating with apocynin. In addition, the amplitude of evoked intracellular Ca2+ concentration transients that was diminished in mdx myocytes was also restored with NOX2 inhibition. Total sarcoplasmic reticulum (SR) Ca2+ content was reduced in mdx hearts and normalized by apocynin treatment. Additionally, NOX2 inhibition decreased the production of spontaneous diastolic calcium release events and decreased the SR calcium leak in mdx myocytes. In addition, nitric oxide (NO) synthase 1 (NOS-1) expression was increased eightfold in mdx hearts compared with wild type. Nevertheless, cardiac NO production was reduced. To test whether this paradox implied NOS-1 uncoupling, we treated cardiac myocytes with exogenous tetrahydrobioterin, along with the NOX inhibitor VAS2870. These agents restored NO production and phospholamban phosphorylation in mdx toward normal. Together, these results demonstrate that, in mdx hearts, NOX2 inhibition improves the SR calcium handling and contractility, partially by recoupling NOS-1. These findings reveal a new layer of nitroso-redox imbalance in dystrophic cardiomyopathy.

scholarly journals Nonlinear Dynamic Modeling of 2-Dimensional Interdependent Calcium and Inositol 1,4,5-Trisphosphate in Cardiac Myocyte

2019 ◽  
Vol 14 (1) ◽  
pp. 290-305 ◽  
Author(s):  
N. Singh ◽  
N. Adlakha
Keyword(s):  
Cardiac Myocyte ◽  
Calcium Release ◽  
Feedback Regulation ◽  
Calcium Oscillations ◽  
The Body ◽  
Calcium Dependent ◽  
Coupled Equations ◽  
Calcium Modulation ◽  
Inositol 1,4,5 Trisphosphate ◽  
The Impact

Calcium (Ca2+) and inositol 1,4,5-trisphosphate (IP3) is critically important actors for a vast array of cellular processes. The most significant of the functions is One of the main functions is communication in all parts of the body which is achieved through cell signaling. Abnormalities in Ca2+signaling have been implicated in clinically important conditions such as heart failure and cardiac arrhythmias. We propose a mathematical model which systematically investigates complex Ca2+and IP3dynamics in cardiac myocyte. This two dimensional model is based on calcium-induced calcium release via inositol 1,4,5-trisphosphate receptors and includes calcium modulation of IP3levels through feedback regulation of degradation and production. Forward-Time Centered-Space method has been used to solve the coupled equations. We were able to reproduce the observed oscillatory patterns in Ca2+as well as IP3signals. The model predicts that calcium-dependent production and degradation of IP3is a key mechanism for complex calcium oscillations in cardiac myocyte. The impact and sensitivity of source, leak, diffusion coefficients on both Ca2+and IP3dynamics have been investigated. The results show that the relationship between Ca2+and IP3dynamics is nonlinear.

scholarly journals MYR1-Dependent Effectors Are the Major Drivers of a Host Cell’s Early Response to Toxoplasma , Including Counteracting MYR1-Independent Effects

mBio ◽  
2018 ◽  
Vol 9 (2) ◽  
Author(s):  
Adit Naor ◽  
Michael W. Panas ◽  
Nicole Marino ◽  
Michael J. Coffey ◽  
Christopher J. Tonkin ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Host Cell ◽  
Expression Profiles ◽  
Parasitophorous Vacuole ◽  
Effector Proteins ◽  
Gene Set Enrichment Analysis ◽  
Host Cells ◽  
Content Type ◽  
Cell Functions ◽  
The Impact

ABSTRACT The obligate intracellular parasite Toxoplasma gondii controls its host cell from within the parasitophorous vacuole (PV) by using a number of diverse effector proteins, a subset of which require the aspartyl protease 5 enzyme (ASP5) and/or the recently discovered MYR1 protein to cross the PV membrane. To examine the impact these effectors have in the context of the entirety of the host response to Toxoplasma , we used RNA-Seq to analyze the transcriptome expression profiles of human foreskin fibroblasts infected with wild-type RH (RH-WT), RHΔ myr1 , and RHΔ asp5 tachyzoites. Interestingly, the majority of the differentially regulated genes responding to Toxoplasma infection are MYR1 dependent. A subset of MYR1 responses were ASP5 independent, and MYR1 function did not require ASP5 cleavage, suggesting the export of some effectors requires only MYR1. Gene set enrichment analysis of MYR1-dependent host responses suggests an upregulation of E2F transcription factors and the cell cycle and a downregulation related to interferon signaling, among numerous others. Most surprisingly, “hidden” responses arising in RHΔ myr1 - but not RH-WT-infected host cells indicate counterbalancing actions of MYR1-dependent and -independent activities. The host genes and gene sets revealed here to be MYR1 dependent provide new insight into the parasite’s ability to co-opt host cell functions. IMPORTANCE Toxoplasma gondii is unique in its ability to successfully invade and replicate in a broad range of host species and cells within those hosts. The complex interplay of effector proteins exported by Toxoplasma is key to its success in co-opting the host cell to create a favorable replicative niche. Here we show that a majority of the transcriptomic effects in tachyzoite-infected cells depend on the activity of a novel translocation system involving MYR1 and that the effectors delivered by this system are part of an intricate interplay of activators and suppressors. Removal of all MYR1-dependent effectors reveals previously unknown activities that are masked or hidden by the action of these proteins.

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