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Microorganisms
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Toxoplasma gondii: More Insights into Host-Pathogen Interactions
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Toxoplasma gondii: More Insights into Host-Pathogen Interactions

A special issue of Microorganisms (ISSN 2076-2607). This special issue belongs to the section "Parasitology".

Deadline for manuscript submissions: closed (30 June 2020) | Viewed by 21279

Special Issue Editor

Dr. Hany Elsheikha

E-Mail Website
Guest Editor
School of Veterinary Medicine and Science, Faculty of Medicine and Health Sciences, University of Nottingham, Sutton Bonington Campus, Loughborough LE12 5RD, UK
Interests: host-parasite interaction; neuropathogens; therapeutics; public health
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Over one-third of the world’s human population have been said to be infected with Toxoplasma gondii. Besides its substantial medical and veterinary significance, this single-cell protozoan parasite has a remarkable ability to evade very powerful host immune defense mechanisms and cause disease. Significant and rapid progress has been made in the last few years in order to discover the factors, pathways, mechanisms, and molecules that shape this complex and dynamic host–pathogen relationship. A greater understanding of the strategies and mechanisms by which this parasite can wreak havoc, shut down multiple essential functions, and reprogram host cell signalling pathways could one day open the door to developing better ways to fighting what can be life-threatening infections, particularly in immunocompromised individuals. In this Special Issue, we hope to publish reviews and research articles that capture the novel aspects of the fascinating and dynamic interaction between T. gondii and its host. Topics that will be considered include, but are not limited to, the analysis of the molecular changes in the structure or function of host cells following T. gondii infection, understanding the host response to infection or to treatment with anti-Toxoplasma drugs, the functional analysis of specific parasite gene(s), and the discovery of new virulence factors or chemical signals that maintain host–parasite interactions

Figure 1. TEM micrograph of Toxoplasma gondii tachyzoites growing inside a vacuole within the host cell.

Dr. Hany Elsheikha
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Microorganisms is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Biomarkers
  • Evolution
  • Gene editing
  • Genomics
  • Host–pathogen interactions
  • Imaging
  • Metabolomics
  • Novel therapeutic strategies
  • Proteomics
  • Single-cell measurements
  • Toxoplasma gondii
  • Transcriptomics
  • Virulence

Published Papers (7 papers)

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Research

22 pages, 7461 KiB  
Article
Structural, Functional, and Metabolic Alterations in Human Cerebrovascular Endothelial Cells during Toxoplasma gondii Infection and Amelioration by Verapamil In Vitro
by Alaa T. Al-sandaqchi, Victoria Marsh, Huw E. L. Williams, Carl W. Stevenson and Hany M. Elsheikha
Microorganisms 2020, 8(9), 1386; https://doi.org/10.3390/microorganisms8091386 - 10 Sep 2020
Cited by 6 | Viewed by 2950
Abstract
Toxoplasma gondii (T. gondii), the causative agent of toxoplasmosis, is a frequent cause of brain infection. Despite its known ability to invade the brain, there is still a dire need to better understand the mechanisms by which this parasite interacts with [...] Read more.
Toxoplasma gondii (T. gondii), the causative agent of toxoplasmosis, is a frequent cause of brain infection. Despite its known ability to invade the brain, there is still a dire need to better understand the mechanisms by which this parasite interacts with and crosses the blood–brain barrier (BBB). The present study revealed structural and functional changes associated with infection and replication of T. gondii within human brain microvascular endothelial cells (BMECs) in vitro. T. gondii proliferated within the BMECs and disrupted the integrity of the cerebrovascular barrier through diminishing the cellular viability, disruption of the intercellular junctions and increasing permeability of the BMEC monolayer, as well as altering lipid homeostasis. Proton nuclear magnetic resonance (1H NMR)-based metabolomics combined with multivariate data analysis revealed profiles that can be attributed to infection and variations in the amounts of certain metabolites (e.g., amino acids, fatty acids) in the extracts of infected compared to control cells. Notably, treatment with the Ca2+ channel blocker verapamil rescued BMEC barrier integrity and restricted intracellular replication of the tachyzoites regardless of the time of treatment application (i.e., prior to infection, early- and late-infection). This study provides new insights into the structural and functional changes that accompany T. gondii infection of the BMECs, and sheds light upon the ability of verapamil to inhibit the parasite proliferation and to ameliorate the adverse effects caused by T. gondii infection. Full article
(This article belongs to the Special Issue Toxoplasma gondii: More Insights into Host-Pathogen Interactions)
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10 pages, 979 KiB  
Communication
Evaluating the Antiparasitic Activity of Novel BPZ Derivatives Against Toxoplasma gondii
by Olivia Hatton, Lea Stitzlein, Richard W. Dudley and Robert A. Charvat
Microorganisms 2020, 8(8), 1159; https://doi.org/10.3390/microorganisms8081159 - 30 Jul 2020
Cited by 3 | Viewed by 2917
Abstract
Prevalence studies revealed that one-third of the human population is chronically infected with Toxoplasma gondii. Presently, such infections are without medical treatment that effectively eradicates the parasite once it is in its latent form. Moreover, the therapeutics used to treat acute infections [...] Read more.
Prevalence studies revealed that one-third of the human population is chronically infected with Toxoplasma gondii. Presently, such infections are without medical treatment that effectively eradicates the parasite once it is in its latent form. Moreover, the therapeutics used to treat acute infections are poorly tolerated by patients and also cause the parasite to convert into long-lasting tissue cysts. Hence, there is a dire need for compounds with antiparasitic activity against all forms of T. gondii. This study examines the antiparasitic capacity of nine novel bisphenol Z (BPZ) derivatives to determine whether they possessed any activity that prevented T. gondii replication. To begin assessing the efficacy of the novel derivatives, parasites were treated with increasing concentrations of the compounds, then doubling assays and MitoTracker staining were performed. Three of the nine compounds demonstrated strong inhibitory activity, i.e., parasite replication significantly decreased with higher concentrations. Additionally, many of the treated parasites exhibited decreases in fluorescent signaling and disruption of mitochondrial morphology. These findings suggest that bisphenol Z compounds disrupt mitochondrial function to inhibit parasite replication and may provide a foundation for the development of new and effective treatment modalities against T. gondii. Full article
(This article belongs to the Special Issue Toxoplasma gondii: More Insights into Host-Pathogen Interactions)
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26 pages, 3222 KiB  
Article
Transcriptome Profiling of Toxoplasma gondii-Infected Human Cerebromicrovascular Endothelial Cell Response to Treatment with Monensin
by Mohammad S. R. Harun, Mica Taylor, Xing-Quan Zhu and Hany M. Elsheikha
Microorganisms 2020, 8(6), 842; https://doi.org/10.3390/microorganisms8060842 - 04 Jun 2020
Cited by 6 | Viewed by 2963
Abstract
Central to the progression of cerebral toxoplasmosis is the interaction of Toxoplasma gondii with the blood-brain barrier (BBB) endothelial cells. In the present work, we tested the hypothesis that inhibition of Wnt pathway signalling by the monovalent ionophore monensin reduces the growth of [...] Read more.
Central to the progression of cerebral toxoplasmosis is the interaction of Toxoplasma gondii with the blood-brain barrier (BBB) endothelial cells. In the present work, we tested the hypothesis that inhibition of Wnt pathway signalling by the monovalent ionophore monensin reduces the growth of T. gondii infecting human brain microvascular endothelial cells (hBMECs) or microglial cells. The anti-parasitic effect of monensin (a Wnt signalling inhibitor) on the in vitro growth of T. gondii tachyzoites was investigated using two methods (Sulforhodamine B staining and microscopic parasite counting). The monensin inhibited T. gondii growth (50% inhibitory concentration [IC50] = 0.61 μM) with a selective index = 8.48 when tested against hBMECs (50% cytotoxic concentration [CC50] = 5.17 μM). However, IC50 of monensin was 4.13 μM with a SI = 13.82 when tested against microglia cells (CC50 = 57.08 μM), suggesting less sensitivity of microglia cells to monensin treatment. The effect of T. gondii on the integrity of the BBB was assessed by the transendothelial electrical resistance (TEER) assay using an in vitro human BBB model. The results showed that T. gondii infection significantly decreased hBMECs’ TEER resistance, which was rescued when cells were treated with 0.1 µM monensin, probably due to the anti-parasitic activity of monensin. We also investigated the host-targeted effects of 0.1 µM monensin on global gene expression in hBMECs with or without T. gondii infection. Treatment of hBMECs with monensin did not significantly influence the expression of genes involved in the Wnt signalling pathway, suggesting that although inhibition of the Wnt signalling pathway did not play a significant role in T. gondii infection of hBMECs, monensin was still effective in limiting the growth of T. gondii. On the contrary, monensin treatment downregulated pathways related to steroids, cholesterol and protein biosynthesis and their transport between endoplasmic reticulum and Golgi apparatus, and deregulated pathways related to cell cycle and DNA synthesis and repair mechanisms. These results provide new insight into the host-modulatory effect of monensin during T. gondii infection, which merits further investigation. Full article
(This article belongs to the Special Issue Toxoplasma gondii: More Insights into Host-Pathogen Interactions)
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18 pages, 9984 KiB  
Article
The Availability of Iron Is Involved in the Murine Experimental Toxoplasma gondii Infection Outcome
by Mário Cézar Oliveira, Loyane Bertagnolli Coutinho, Marcos Paulo Oliveira Almeida, Marisol Pallete Briceño, Ester Cristina Borges Araujo and Neide Maria Silva
Microorganisms 2020, 8(4), 560; https://doi.org/10.3390/microorganisms8040560 - 14 Apr 2020
Cited by 12 | Viewed by 2798
Abstract
Iron is an important constituent of our environment, being necessary for both mammalian and pathogenic protozoa survival. Iron-containing proteins exert a wide range of biological processes such as biodegradation and biosynthesis, as well as immune function, fetal development, and physical and mental well-being. [...] Read more.
Iron is an important constituent of our environment, being necessary for both mammalian and pathogenic protozoa survival. Iron-containing proteins exert a wide range of biological processes such as biodegradation and biosynthesis, as well as immune function, fetal development, and physical and mental well-being. This work aimed to investigate the effect of iron deprivation in Toxoplasma gondii infection outcome. C57BL/6 mice were orally infected with T. gondii and treated with an iron chelator, deferoxamine, or supplemented with iron (ferrous sulfate), and the parasitism as well as immunological and histological parameters were analyzed. It was observed that the infection increased iron accumulation in the organs, as well as systemically, and deferoxamine treatment diminished the iron content in serum samples and intestine. The deferoxamine treatment decreased the parasitism and inflammatory alterations in the small intestine and lung. Additionally, they partially preserved the Paneth cells and decreased the intestinal dysbiosis. The ferrous sulfate supplementation, despite not significantly increasing the parasite load in the organs, increased the inflammatory alterations in the liver. Together, our results suggest that iron chelation, which is commonly used to treat iron overload, could be a promising medicine to control T. gondii proliferation, mainly in the small intestine, and consequently inflammation caused by infection. Full article
(This article belongs to the Special Issue Toxoplasma gondii: More Insights into Host-Pathogen Interactions)
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20 pages, 7701 KiB  
Article
iTRAQ-based Quantitative Proteomics Analysis Identifies Host Pathways Modulated during Toxoplasma gondii Infection in Swine
by Jun-Jun He, Jun Ma, Jin-Lei Wang, Fu-Kai Zhang, Jie-Xi Li, Bin-Tao Zhai, Hany M. Elsheikha and Xing-Quan Zhu
Microorganisms 2020, 8(4), 518; https://doi.org/10.3390/microorganisms8040518 - 05 Apr 2020
Cited by 8 | Viewed by 2706
Abstract
Toxoplasma gondii is a leading cause of foodborne illness and consumption of undercooked pig meat is a major risk factor for acquiring toxoplasmosis, which causes a substantial burden on society. Here, we used isobaric tags for relative and absolute quantification (iTRAQ) labelling coupled [...] Read more.
Toxoplasma gondii is a leading cause of foodborne illness and consumption of undercooked pig meat is a major risk factor for acquiring toxoplasmosis, which causes a substantial burden on society. Here, we used isobaric tags for relative and absolute quantification (iTRAQ) labelling coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify cellular proteins and pathways altered during T. gondii infection in pigs. We also used parallel reaction monitoring-based LC-MS/MS to verify the levels of protein expression of infected spleens and mesenteric lymph nodes (MLNs). At 6 days post-infection (dpi), 156, 391, 170, 292, and 200 differentially expressed proteins (DEPs) were detected in the brain, liver, lung, MLNs and spleen, respectively. At 18 dpi, 339, 351, 483, 388, and 303 DEPs were detected in the brain, liver, lung, MLNs and spleen, respectively. Although proteins involved in immune responses were upregulated in all infected tissues, protein expression signature in infected livers was dominated by downregulation of the metabolic processes. By weighted gene co-expression network analysis, we could further show that all proteins were clustered into 25 co-expression modules and that the pink module significantly correlated with the infection status. We also identified 163 potential anti-T. gondii proteins (PATPs) and provided evidence that two PATPs (HSP70.2 and PDIA3) can reduce T. gondii burden in porcine macrophages in vitro. This comprehensive proteomics analysis reveals new facets in the pathogenesis of T. gondii infection and identifies key proteins that may contribute to the pig’s defense against this infection. Full article
(This article belongs to the Special Issue Toxoplasma gondii: More Insights into Host-Pathogen Interactions)
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13 pages, 3852 KiB  
Article
RHΔgra17Δnpt1 Strain of Toxoplasma gondii Elicits Protective Immunity Against Acute, Chronic and Congenital Toxoplasmosis in Mice
by Qin-Li Liang, Li-Xiu Sun, Hany M. Elsheikha, Xue-Zhen Cao, Lan-Bi Nie, Ting-Ting Li, Tao-Shan Li, Xing-Quan Zhu and Jin-Lei Wang
Microorganisms 2020, 8(3), 352; https://doi.org/10.3390/microorganisms8030352 - 01 Mar 2020
Cited by 14 | Viewed by 2765
Abstract
In the present study, a dense granule protein 17 (gra17) and novel putative transporter (npt1) double deletion mutant of Toxoplasma gondii RH strain was engineered. The protective efficacy of vaccination using RHΔgra17Δnpt1 tachyzoites against acute, chronic, and [...] Read more.
In the present study, a dense granule protein 17 (gra17) and novel putative transporter (npt1) double deletion mutant of Toxoplasma gondii RH strain was engineered. The protective efficacy of vaccination using RHΔgra17Δnpt1 tachyzoites against acute, chronic, and congenital toxoplasmosis was studied in a mouse model. Immunization using RHΔgra17Δnpt1 induced a strong humoral and cellular response, as indicated by the increased levels of anti-T. gondii specific IgG, interleukin 2 (IL-2), IL-10, IL-12, and interferon-gamma (IFN-γ). Vaccinated mice were protected against a lethal challenge dose (103 tachyzoites) of wild-type homologous (RH) strain and heterologous (PYS and TgC7) strains, as well as against 100 tissue cysts or oocysts of Pru strain. Vaccination also conferred protection against chronic infection with 10 tissue cysts or oocysts of Pru strain, where the numbers of brain cysts in the vaccinated mice were significantly reduced compared to those detected in the control (unvaccinated + infected) mice. In addition, vaccination protected against congenital infection with 10 T. gondii Pru oocysts (administered orally on day 5 of gestation) as shown by the increased litter size, survival rate and the bodyweight of pups born to vaccinated dams compared to those born to unvaccinated + infected dams. The brain cyst burden of vaccinated dams was significantly lower than that of unvaccinated dams infected with oocysts. Our data show that T. gondii RHΔgra17Δnpt1 mutant strain can protect mice against acute, chronic, and congenital toxoplasmosis by balancing inflammatory response with immunogenicity. Full article
(This article belongs to the Special Issue Toxoplasma gondii: More Insights into Host-Pathogen Interactions)
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19 pages, 5787 KiB  
Article
Label-Free Quantitative Acetylome Analysis Reveals Toxoplasma gondii Genotype-Specific Acetylomic Signatures
by Ze-Xiang Wang, Rui-Si Hu, Chun-Xue Zhou, Jun-Jun He, Hany M. Elsheikha and Xing-Quan Zhu
Microorganisms 2019, 7(11), 510; https://doi.org/10.3390/microorganisms7110510 - 30 Oct 2019
Cited by 8 | Viewed by 2981
Abstract
Distinct genotypic and pathogenic differences exist between Toxoplasma gondii genotypes. For example, genotype I is highly virulent, whereas genotype II and genotype III are less virulent. Moreover, Chinese 1 genotype (ToxoDB#9) is also virulent. Here, we compare the acetylomes of genotype 1 (RH [...] Read more.
Distinct genotypic and pathogenic differences exist between Toxoplasma gondii genotypes. For example, genotype I is highly virulent, whereas genotype II and genotype III are less virulent. Moreover, Chinese 1 genotype (ToxoDB#9) is also virulent. Here, we compare the acetylomes of genotype 1 (RH strain) and Chinese 1 genotype (ToxoDB#9, PYS strain) of T. gondii. Using mass spectrometry enriched for acetylated peptides, we found a relationship between the levels of protein acetylation and parasite genotype-specific virulence. Notably, lysine acetylation was the largest (458 acetylated proteins) in RH strain, followed by PYS strain (188 acetylated proteins), whereas only 115 acetylated proteins were detected in PRU strain. Our analysis revealed four, three, and four motifs in RH strain, PRU strain and PYS strain, respectively. Three conserved sequences around acetylation sites, namely, xxxxxKAcHxxxx, xxxxxKAcFxxxx, and xxxxGKAcSxxxx, were detected in the acetylome of the three strains. However, xxxxxKAcNxxxx (asparagine) was found in RH and PYS strains but was absent in PRU strain. Our analysis also identified 15, 3, and 26 differentially expressed acetylated proteins in RH strain vs. PRU strain, PRU strain vs. PYS strain and PYS strain vs. RH strain, respectively. KEGG pathway analysis showed that a large proportion of the acetylated proteins are involved in metabolic processes. Pathways for the biosynthesis of secondary metabolites, biosynthesis of antibiotics and microbial metabolism in diverse environments were featured in the top five enriched pathways in all three strains. However, acetylated proteins from the virulent strains (RH and PYS) were more enriched in the pyruvate metabolism pathway compared to acetylated proteins from PRU strain. Increased levels of histone-acetyl-transferase and glycyl-tRNA synthase were detected in RH strain compared to PRU strain and PYS strain. Both enzymes play roles in stress tolerance and proliferation, key features in the parasite virulence. These findings reveal novel insight into the acetylomic profiles of major T. gondii genotypes and provide a new important resource for further investigations of the roles of the acetylated parasite proteins in the modulation of the host cell response to the infection of T. gondii. Full article
(This article belongs to the Special Issue Toxoplasma gondii: More Insights into Host-Pathogen Interactions)
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