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Proteomics and their Analyses. a-b. Proteins differentially expressed during parasite infection of L-NSC (a) or S-NSC (b). ATXN2L, Ataxin 2-like; NSC2, Niemann-Pick disease, type C2; FXR1, Fragile X Mental Retardation Autosomal Homolog 1; WDFY1, WD Repeat And FYVE Domain Containing 1; UBE3A, Ubiquitin Protein Ligase E3A; USP8, Ubiquitin Specific Peptidase 8; PPP4C, Protein Phosphatase 4 Catalytic Subunit). (c) Left panel, number of differentially expressed proteins (DEPs) in S-NSC infected with T. gondii types I, II and III; right panel, GO Biological Processes significantly overrepresented (p-value < 0.01) in the set of 3,359 proteins differentially expressed in infected S-NSC compared with their respective uninfected controls (>2-fold change and false discovery rate <0.1). Nominal p-values were utilized for KEGG and GO analyses. Pathways that were robust to Benjamini Hochberg correction also are shown in Supplement B: Table S15.
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One third of humans are infected lifelong with the brain-dwelling, protozoan parasite, Toxoplasma gondii. Approximately fifteen million of these have congenital toxoplasmosis. Although neurobehavioral disease is associated with seropositivity, causality is unproven. To better understand what this parasite does to human brains, we performed a compre...
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... gene expression were also evident by miR-seq for MM6, S-NSC and S-NDC cells at 18 hours post-infection (Figs 3 and 4 and Supplement B: Tables S11 and S12). These included mirs 139, 132, 29a, 107, 218, 143, 155, 199a, 21, 16, 181b-1. L-NSC and S-NSC infections with Type I, II, III parasites were also studied using iTRAQ quantitative pro- teomics ( Fig. 5). Differential protein expression analysis of L-NSC cells identified only three primary candi- date proteins with significant fold change increases in infected cells. These proteins were Ataxin 2-like protein (ATXN2L); Fragile X-related protein 1 (FXR1); and Niemann-Pick-like protein (NPC2) (Fig. 5a, Supplement B: Table S4). An IPA ...
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... studied using iTRAQ quantitative pro- teomics ( Fig. 5). Differential protein expression analysis of L-NSC cells identified only three primary candi- date proteins with significant fold change increases in infected cells. These proteins were Ataxin 2-like protein (ATXN2L); Fragile X-related protein 1 (FXR1); and Niemann-Pick-like protein (NPC2) (Fig. 5a, Supplement B: Table S4). An IPA later showed how these three proteins were linked to transcriptomic infectomes and identified congenital toxoplasmosis susceptibility genes ( Figs 6, 7). These proteomics and transcriptomics (Figs 3-5) defined empirically, responses of human L-NSC to infection with T. ...
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... infection ( Table S15). In summary, S-NSC pro- teomics, pathway and GO enrichment analyses showed signaling pathways impacting on cell death, TOR, protein transport/localization and RNA splicing. Oxidation reduction, vesicle mediated transport, iron homeostasis and glucose metabolism were also influenced, some differentially by parasite type (Fig. 5c). Consistent with these enrichment results, prediction of alternative spliced isoforms in our transcriptomics datasets identified a number of candidate genes predicted 51 to be differentially spliced during parasite infections (Supplement B: Table S14). Each of the three ill children had new myoclonic-"infantile" spasms, or ...
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... Our transcriptomic and proteomic analyses indicated that this parasite alters neddylation (NEDD8) and ubiquitination which are key in clearing misfolded proteins, neuronal cell viability, and synaptic plasticity (Figs 3, 4, 9 and 11c). In the proteomics analyses, we also found that T. gondii modified alternative splicing (Fig. 5) and that an rMATS analysis 51 predicted transcripts that are alternatively spliced based on the S-NSC ...
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... the quantitative proteomics with L-NSC (Fig. 5a), ATXN2L, FXR1, and NPC2 were modulated. ATXN2L is a paralog of Ataxin 2, a protein that causes spinocerebellar ataxia type 2 72 . It has been shown that ATXN2L is functionally similar to Ataxin 2 with respect to RNA metabolism and also plays a role in the regulation of stress granules and processing bodies in mammalian cells 73 . ...
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... the quantitative proteomics of S-NSC (Fig. 5b) many more genes transcripts were modulated. Some of particular interest are shown in Fig. 5b as follows: WDFY1 and PPP4C, two proteins known to modulate NFκB activity, a key factor to control parasite infections, were downregulated in infected S-NSC (Fig. 5b). WDFY1 induces TLR3-and TLR4-mediated activation of NFκB and the production ...
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... the quantitative proteomics of S-NSC (Fig. 5b) many more genes transcripts were modulated. Some of particular interest are shown in Fig. 5b as follows: WDFY1 and PPP4C, two proteins known to modulate NFκB activity, a key factor to control parasite infections, were downregulated in infected S-NSC (Fig. 5b). WDFY1 induces TLR3-and TLR4-mediated activation of NFκB and the production of type I interferons and inflam- matory cytokines 76 , while PPP4C is the catalytic subunit ...
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... the quantitative proteomics of S-NSC (Fig. 5b) many more genes transcripts were modulated. Some of particular interest are shown in Fig. 5b as follows: WDFY1 and PPP4C, two proteins known to modulate NFκB activity, a key factor to control parasite infections, were downregulated in infected S-NSC (Fig. 5b). WDFY1 induces TLR3-and TLR4-mediated activation of NFκB and the production of type I interferons and inflam- matory cytokines 76 , while PPP4C is the catalytic subunit of protein phosphatase 4, a protein implicated in the activation of NFκB-mediated transcription 77 . This strongly suggests that T. gondii inhibits the human host NFkB ...
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... cell cycle are especially noteworthy in the KEGG pathways for S-NSC (Fig. 2c). Transcriptomic analysis of L-NSC reveals pathways associated with Alzheimer's, Parkinson's and Huntington diseases and disruption of oxidative phosphorylation. Also alternative splicing pathways which might cause protein misfolding and neurologic diseases are affected (Fig. 5). Transcriptomics, proteomics, and cluster deconvolution identified alterations in neddylation and ubiquitination key in clearing misfolded pro- teins, neuronal cell viability, and synaptic plasticity (Figs 3-5, 9). We are investigating whether T. gondii causes alternative splicing which can be a central cause of protein misfolding, ...
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Upon invasion of host cells, the ubiquitous pathogen Toxoplasma gondii manipulates several host processes, including re-organization of host organelles, to create a replicative niche. Host mitochondrial association to T. gondii parasitophorous vacuoles is rapid and has roles in modulating host immune responses. Here gene expression profiling of T....
Estradiol (E2) plays a crucial and intricate role during pregnancy to mediate several aspects of the pregnancy process. A perplexing phenomenon in congenital toxoplasmosis is that the severity of Toxoplasma gondii (T. gondii)-mediated adverse pregnancy outcome is closely related with time of primary maternal infection during pregnancy. In this stud...
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... Toxoplasma gondii is estimated to infect one in three people around the world, 1 and infection in the immunocompromised can have devastating results. 2 The immune response to the acute stage of infection is characterised by early recruitment of innate immune cells including neutrophils to sites of infection and innate cytokine production. 3,4 Neutrophils produce some vital early cytokines and chemokines that encourage additional cell recruitment and are able to directly kill the parasite through mechanisms like phagocytosis, 5 reactive oxygen species (ROS) production, 6 and the process of NETosis to ensnare and kill free-floating pathogens. ...
The protozoan parasite Toxoplasma gondii infects approximately 2.5 billion people worldwide. Infection induces a rapid dissemination of parasites throughout the body followed by the formation of lifelong cysts within neurons of the host brain. Both stages require a dynamic immune response comprised of both innate and adaptive cells. Neutrophils are a primary responding cell to acute infection and have been observed in the brain during murine chronic infection. Previous studies investigating human neutrophils found that invasion by Toxoplasma tachyzoites inhibits apoptosis of neutrophils, prolonging their survival under inflammatory conditions. Here, we demonstrate the differentiation of two distinct subsets following exposure of human neutrophil‐like‐cells (HNLC) to Toxoplasma cysts. In vitro stimulation and imaging studies show cyst‐specific induction of cytokines and cyst clearance by HNLCs. Further testing demonstrates that aged HNLCs perform less phagocytosis of cysts compared to non‐aged HNLCs. In conclusion, this study identifies a novel response of HNLCs to Toxoplasma cysts and may indicate a role for neutrophils in the clearance of cysts during human infection with Toxoplasma.
... The observed DBH down-regulation is likely to be a minimal baseline as it remains possible that vesicles may stick to the transwell membrane and that EV passage is restricted. Parasite restriction to the upper reservoir of the 0. 4 www.nature.com/scientificreports/ www.nature.com/scientificreports/ ...
Infection with the protozoan Toxoplasma gondii induces changes in neurotransmission, neuroinflammation, and behavior, yet it remains elusive how these changes come about. In this study we investigated how norepinephrine levels are altered by infection. TINEV (Toxoplasma-induced neuronal extracellular vesicles) isolated from infected noradrenergic cells down-regulated dopamine ß-hydroxylase (DBH) gene expression in human and rodent cells. Here we report that intracerebral injection of TINEVs into the brain is sufficient to induce DBH down-regulation and distrupt catecholaminergic signalling. Further, TINEV treatment induced hypermethylation upstream of the DBH gene. An antisense lncRNA to DBH was found in purified TINEV preparations. Paracrine signalling to induce transcriptional gene silencing and DNA methylation may be a common mode to regulate neurologic function.
... However, when the parasite is not eliminated from the host, it results in the long-lasting presence of tissue cysts, located mainly in the central nervous system (CNS), muscles, and the eye 1 . The long-term presence of the parasite carries the risk of permanent damage to the eye, the brain, and is also correlated with the occurrence of serious nervous disorders; schizophrenia, Parkinson's disease, or epilepsy [5][6][7][8][9][10] . Toxoplasmosis is also associated with serious consequences in people with immune system dysfunction (HIV-positive people, AIDS patients, chemotherapy/transplant patients) [11][12][13][14][15] . ...
A safer treatment for toxoplasmosis would be achieved by improving the selectivity profile of novel chemotherapeutics compared to the standard therapy pyrimethamine (PYR) and sulfadiazine (SDZ). We previously reported on the identification of the compounds with imidazole-thiosemicarbazide scaffold as potent and selective anti-Toxoplasma gondii (T. gondii) agents. In our current research, we report on the optimisation of this chemical scaffold leading to the discovery cyclic analogue 20 b with s-triazole core structure. This compound displayed prominent CC30 to IC50 selectivity index (SI) of 70.72, making it 160-fold more selective than SDZ, 11-fold more selective than PYR, and 4-fold more selective than trimethoprim (TRI). Additionally, this compound possesses prerequisite drug-like anti-Toxoplasma properties to advance into preclinical development; it showed ability to cross the BBB, did not induce genotoxic and haemolytic changes in human cells, and as well as it was characterised by low cellular toxicity.
... This has been observed in laboratory settings for rodents [50,51], and even in the wild for larger animals [52]. Epidemiological studies and meta-analyses have shown that T. gondii seropositivity can be associated with a number of mental health disorders, including schizophrenia, but also epilepsy and neurodegenerative diseases [53], although causality has not been firmly established. So far, there is no clear experimental demonstration of the direct effects of T. gondii on neurons and their functions, and few evidence of the cellular mechanisms that are dysregulated by the longterm establishment of this parasite in the brain [54]. ...
Toxoplasma gondii is a parasitic protist infecting a wide group of warm-blooded animals, ranging from birds to humans. While this infection is usually asymptomatic in healthy individuals, it can also lead to severe ocular or neurological outcomes in immunocompromised individuals or in developing fetuses. This obligate intracellular parasite has the ability to infect a considerable range of nucleated cells and can propagate in the intermediate host. Yet, under the pressure of the immune system it transforms into an encysted persistent form residing primarily in the brain and muscle tissues. Encysted parasites, which are resistant to current medication, may reactivate and give rise to an acute infection. The clinical outcome of toxoplasmosis depends on a complex balance between the host immune response and parasite virulence factors. Susceptibility to the disease is thus determined by both parasite strains and host species. Recent advances on our understanding of host cell-parasite interactions and parasite virulence have brought new insights into the pathophysiology of T. gondii infection and are summarized here.
... When women acquire T. gondii infection more than 6 months prior to gestation, risk of transmission to the fetus is considerably reduced. However, preventable and treatable congenital, ocular and postnatal T. gondii infection is not curable and persist in all infected persons [5,7,8]. ...
Toxoplasmosis is a common parasitic infection caused by an obligate intracellular protozoan, Toxoplasma gondii. Prevalence and risk factors of T. gondii infection in women of childbearing age in Osun State, Nigeria are unknown. This study was aimed to determine the seroprevalence and potential risk factors in acquiring T. gondii infection by women of childbearing age in Osun State, Nigeria. A community-based cross-sectional study was conducted from May 2019 to December 2019 in childbearing age women. Sera of 415 women aged 18–49 years randomly selected were collected and analyzed by enzyme-linked immunosorbent assay (ELISA) test. A questionnaire survey was administered for all study participants to collect socio- demographic and risk factors data. The study revealed that the overall seroprevalence of T. gondii infection was 76.63%, which comprised 6.02% positivity for anti-T. gondii IgM (25/ 415), 44.10% for IgG (183/415) and 26.51% for IgG plus IgM (110/415). Seroprevalence of IgM antibodies to T. gondii (6.02%) suggested recent infections. Women residing in rural communities and women of Islam religion showed significant association with anti-T. gondii seropositivity (p < 0.05). Residence location and women who are of Islam religion are risk factors to acquire T. gondii infection. Hence, health education and awareness on the disease and its transmission to women of childbearing age group in general and pregnant women in particular should be created during antenatal follow up to reduce the risk of T. gondii infection in pregnant women.
... In addition to potential modulation of dopamine, T. gondii infection reportedly affects other neurotransmitter systems such as GABA [52], serotonin [53], noradrenaline [53], nitric oxide [54,55], kynurenic acid (KYNA) [56], glutamate [57], and the level of proinflammatory cytokines [58]. It is also known that T. gondii infection shares transcriptional pathways which overlap other CNS disease states [59]. Taken together, there are a number of possible pathways potentially disrupted by parasite infection which can account for observed differences in model organism and potentially in humans. ...
The intracellular parasite Toxoplasma gondii is estimated to infect up to 30% of the world population, leading to lifelong chronic infection of the brain and muscle tissue. Although most latent T. gondii infections in humans have traditionally been considered asymptomatic, studies in rodents suggest phenotypic neurological changes are possible. Consequently, several studies have examined the link between T. gondii infection and diseases such as schizophrenia, epilepsy, depression, bipolar disorder, dysphoria, Alzheimer’s disease, Parkinson’s disease, and obsessive-compulsive disorder (OCD). To date, there is varying evidence of the relationship of T. gondii to these human neurological or neurobehavioral disorders. A thorough review of T. gondii literature was conducted to highlight and summarize current findings. We found that schizophrenia was most frequently linked to T. gondii infection, while sleep disruption showed no linkage to T. gondii infection, and other conditions having mixed support for a link to T. gondii. However, infection as a cause of human neurobehavioral disease has yet to be firmly established.
... In particular, toxoplasmosis is a significant burden to immunocompromised 21 individuals and to infants via maternal transmission 22 . While several reports exist that evaluate the interaction of Toxoplasma with co-occurring diseases [23][24][25] , it remains unclear as to how does Toxoplasma infection impacts progression of the common co-occurring diseases receiving treatments in a clinical setting and whether treatment failure or disease progression or other causes leads to the observed associations. There are few studies that evaluate the efficacy of anti-Toxoplasma agents in the presence of other treatments 26 . ...
Adverse outcomes associated with the treatment of Toxoplasma gondii infections in patients with various health backgrounds have not been characterized. The aim of this study was to identify the adverse outcomes and adverse events associated with the current clinical treatments of Toxoplama gondii infections using real world data reported to the FDA adverse event reporting system (FAERS). Data submitted to FAERS between 2013 and 2019 was retrieved and analyzed. Reporting odds ratio of death was calculated for the drugs having ≥ 25 reports of adverse outcomes. The adverse event profiles for the same drugs were analyzed and the reporting odds ratio was calculated relative to all other drugs used in the treatment of Toxoplasma infections. There were 503 cases reporting the treatment of Toxoplasma infections in the FAERS database. Death (DE) was the adverse outcome in 102 reports, of which 23 (22.5%) anti- Toxoplasma drugs were listed as the primary suspect drug (PS). Clindamycin (2.04; 1.07–3.90) followed by pyrimethamine (1.53; 0.99–2.36) were the most likely to be associated with death. Adverse events analysis suggest that sulfonamides formulations may have a less favorable safety profile. Our study represents the first real-world analysis of adverse outcomes and events associated with the treatment of Toxoplasma infections. Our findings support the need to better understand the current first-line agents for Toxoplasma infections, in addition to underscoring the need to identify safer regimens.
... tissue infection sites including the lungs and GI system, and can lead to a CNS Parkinsonian phenotype. With evidence growing for neurotropism of the SARS-CoV-2 coronavirus and potentially for many other emerging viruses, it is important to determine the precise mechanisms by which infectious agents and EMVs may contribute to latent disease, including neurodegenerative diseases and cancers that may arise later in life [9] . ...
... Furthermore, it is also known that T. gondii affects the human brain in many pathways related to epilepsy, neurodegeneration, and cancer. A positive regulation of miR-132 has been reported in the human neuroepithelial cell line infected with RH-2F, PRU, and CTG strains which have been related to a modulation in the expression of genes involved in the metabolism of dopamine, such as apoptotic protease-activating F-factor 1 (APAF1), Kirsten Rat Sarcoma (KRAS), MAPK3 and PPP2R5E Ngô et al. 2017). Finally, it has been recently reviewed that this parasite also features its own miRNA processing system and possesses the capacity to secret exosomes that contain miRNAs (Menard et al. 2019). ...
MicroRNAs (miRNAs) are a group of small noncoding RNA molecules with significant capacity to regulate the gene expression at the post-transcriptional level in a sequence-specific manner either through translation repression or mRNA degradation triggering a fine-tuning biological impact. They have been implicated in several processes, including cell growth and development, signal transduction, cell proliferation and differentiation, metabolism, apoptosis, inflammation, and immune response modulation. However, over the last few years, extensive studies have shown the relevance of miRNAs in human pathophysiology. Common human parasitic diseases, such as Malaria, Leishmaniasis, Amoebiasis, Chagas disease, Schistosomiasis, Toxoplasmosis, Cryptosporidiosis, Clonorchiasis, and Echinococcosis are the leading cause of death worldwide. Thus, identifying and characterizing parasite-specific miRNAs and their host targets, as well as host-related miRNAs, are important for a deeper understanding of the pathophysiology of parasite-specific diseases at the molecular level. In this review, we have demonstrated the impact of human microRNAs during host−parasite interaction as well as their potential to be used for diagnosis and prognosis purposes.
... Eventually, "disease deconvolution" which identifies correlations between epilepsy and parasite-brain interactions, movement disorders, Alzheimer's as well as cancer. This "reconstruction-deconvolution" provides templates of the progenitor cells' potentiating influences and components affecting human brain parasitism and disorders (12) . Little research has been done on the incidence of people suffering from heart disease may be involved in Toxoplasma or may be conducive to these injuries and therefore has been proven that there is a direct relationship with Toxoplasma infection and cases of heart disease and this report works for the first time in Iraq. ...
Toxoplasmosis is one of the risky infection my lead to cardiovascular diseases. One hundred therein patients samples were collected with Heart Diseases and there were infected with Toxoplasmosis, in Baghdad educational Hospital from period 1 st January 2019 to 1 st September 2019. The results show that prevalence of Toxoplasma gondii among Hypertensive disease and Myocardiopathy with Heart Diseases. The genotype of MYLK3 exon to Human cardiac gene by gel electrophoresis, Lane M markers correspond to 500 bp ladder lane 2 of gene band with 600bp. Mutation occurrence in exon 8 the gene sequence CCCAGCCGG were change to CCCATCCGG, and in exon 9 the change occurrence in sequence CTCAAGCCGGAG to CTCAAGGTACAA.
