scholarly journals The host brain is permissive to colonization by Toxoplasma gondii

2020 ◽  
Author(s):  
CJ. Wincott ◽  
G. Sritharan ◽  
M. Bunyan ◽  
E. Alves ◽  
HJ. Benns ◽  
...  
Keyword(s):  
Population Structure ◽  
Toxoplasma Gondii ◽  
Cell Types ◽  
Intervention Strategies ◽  
Evolutionary Strategy ◽  
Pathogen Population ◽  
Persister Cells ◽  
Host Blood ◽  
Cellular Barcoding ◽  
Host Brain

SummaryPathogenic infections and the diseases they cause are defined by invasion and colonization of distinct host cell types and tissue niches. In the case of viruses and bacteria, molecular and cellular barcoding has shaped our understanding of within-host pathogen population dynamics, and informed therapeutic intervention strategies. Host brain colonization is a clinically untreatable feature of persistent infection by the eukaryotic pathogen Toxoplasma gondii, and the process remains poorly understood. The host blood-brain barrier is expected to physically restrict parasite colonization of this tissue niche and force the infection through a selection bottleneck, however tools and technologies to test this hypothesis have not been available. Here, we have developed a simple CRISPR-based method to barcode Toxoplasma parasites, and then used complex libraries of barcoded parasites to define how the different phases of an infection shape the pathogen population structure. Unexpectedly, we have discovered that the murine host brain does not restrict parasite colonization, with the population structure predominantly shaped by a bottleneck experienced during the acute phase of infection. These data support an evolutionary strategy to maximize genetic diversity of parasite persister cells within the intermediate host brain for subsequent transmission into the definitive feline host.

scholarly journals Hydroxylamine and Carboxymethoxylamine Can Inhibit Toxoplasma gondii Growth through an Aspartate Aminotransferase-Independent Pathway

2020 ◽  
Vol 64 (3) ◽  
Author(s):  
Jixu Li ◽  
Huanping Guo ◽  
Eloiza May Galon ◽  
Yang Gao ◽  
Seung-Hun Lee ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Drug Targets ◽  
Protozoan Parasite ◽  
Cell Types ◽  
Lytic Cycle ◽  
Type I ◽  
Content Type ◽  
Mechanism Of Inhibition

ABSTRACT Toxoplasma gondii is an obligate intracellular protozoan parasite and a successful parasitic pathogen in diverse organisms and host cell types. Hydroxylamine (HYD) and carboxymethoxylamine (CAR) have been reported as inhibitors of aspartate aminotransferases (AATs) and interfere with the proliferation in Plasmodium falciparum. Therefore, AATs are suggested as drug targets against Plasmodium. The T. gondii genome encodes only one predicted AAT in both T. gondii type I strain RH and type II strain PLK. However, the effects of HYD and CAR, as well as their relationship with AAT, on T. gondii remain unclear. In this study, we found that HYD and CAR impaired the lytic cycle of T. gondii in vitro, including the inhibition of invasion or reinvasion, intracellular replication, and egress. Importantly, HYD and CAR could control acute toxoplasmosis in vivo. Further studies showed that HYD and CAR could inhibit the transamination activity of rTgAAT in vitro. However, our results confirmed that deficiency of AAT in both RH and PLK did not reduce the virulence in mice, although the growth ability of the parasites was affected in vitro. HYD and CAR could still inhibit the growth of AAT-deficient parasites. These findings indicated that HYD and CAR inhibition of T. gondii growth and control of toxoplasmosis can occur in an AAT-independent pathway. Overall, further studies focusing on the elucidation of the mechanism of inhibition are warranted. Our study hints at new substrates of HYD and CAR as potential drug targets to inhibit T. gondii growth.

scholarly journals Mycelial Compatibility Grouping and Aggressiveness of Sclerotinia sclerotiorum

Plant Disease ◽  
2004 ◽  
Vol 88 (4) ◽  
pp. 325-332 ◽  
Author(s):  
L. S. Kull ◽  
W. L. Pedersen ◽  
D. Palmquist ◽  
G. L. Hartman
Keyword(s):  
Population Structure ◽  
Disease Management ◽  
Sclerotinia Sclerotiorum ◽  
Stem Rot ◽  
Management Systems ◽  
Sclerotinia Stem Rot ◽  
Pathogen Population ◽  
Causal Organism ◽  
Soybean Field ◽  
Mycelial Compatibility

Population variability of Sclerotinia sclerotiorum, the causal organism of Sclerotinia stem rot of soybean, was determined by mycelial compatibility grouping (MCG) and isolate aggressiveness comparisons. MCG and aggressiveness of S. sclerotiorum isolates from diverse hosts and geographic locations (Diverse Set, 24 isolates), from a soybean field in Argentina (Argentine Set, 21 isolates), and from soybean fields in DeKalb and Watseka, Illinois (DeKalb Set, 124 isolates, and Watseka Set, 130 isolates) were assessed. Among 299 isolates tested, 42 MCGs were identified, and 61% were represented by single isolates observed at single locations. Within the Diverse Set, 17 MCGs were identified; 1 MCG consisted of six isolates, and 16 MCGs consisted of one isolate each. Nine MCGs were identified within the Argentine field with two MCGs composed of either five or six isolates, two MCGs composed of two isolates, and the remaining composed of one isolate each. Each Illinois field was a mosaic of MCGs, but MCG frequencies differed between the two fields. Common MCGs were identified among the Diverse, DeKalb, and Watseka Sets, but no MCGs within the Argentine Set were observed with other sets. MCG 8 was the most frequently sampled and widely dispersed MCG and occurred at a frequency of 29, 36, and 62% in the Diverse, DeKalb, and Watseka Sets, respectively. Variation in isolate aggressiveness was assessed using a limited-term, plug inoculation technique. Isolate aggressiveness varied (P = 0.001) within the Diverse, Argentine, DeKalb, and Watseka Sets. Within widely dispersed MCGs, isolate aggressiveness varied (P ≤ 0.10); however, within locally observed MCGs detected only in single fields, isolate aggressiveness did not vary. Additionally, individual MCGs within the DeKalb and Watseka Sets differed in isolate aggressiveness. Using six soybean cultivars and six S. sclerotiorum isolates, no cultivar-isolate interaction was detected, but resistant and susceptible cultivars performed similarly when inoculated with either less or highly aggressive isolates. Pathogen population structure and variability in isolate aggressiveness may be important considerations in disease management systems.

scholarly journals Genetic diversity of Toxoplasma gondii in animals and humans

2009 ◽  
Vol 364 (1530) ◽  
pp. 2749-2761 ◽  
Author(s):  
L. David Sibley ◽  
Asis Khan ◽  
James W. Ajioka ◽  
Benjamin M. Rosenthal
Keyword(s):  
Population Structure ◽  
Toxoplasma Gondii ◽  
North America ◽  
Companion Animals ◽  
Complex Life Cycle ◽  
South American ◽  
Sexual Recombination ◽  
Severe Infections ◽  
Vertebrate Hosts ◽  
Human Infections

Toxoplasma gondii is one of the most widespread parasites of domestic, wild, and companion animals, and it also commonly infects humans. Toxoplasma gondii has a complex life cycle. Sexual development occurs only in the cat gut, while asexual replication occurs in many vertebrate hosts. These features combine to create an unusual population structure. The vast majority of strains in North America and Europe fall into three recently derived, clonal lineages known as types I, II and III. Recent studies have revealed that South American strains are more genetically diverse and comprise distinct genotypes. These differences have been shaped by infrequent sexual recombination, population sweeps and biogeography. The majority of human infections that have been studied in North America and Europe are caused by type II strains, which are also common in agricultural animals from these regions. In contrast, several diverse genotypes of T. gondii are associated with severe infections in humans in South America. Defining the population structure of T. gondii from new regions has important implications for transmission, immunogenicity and pathogenesis.

scholarly journals Neurophysiological Changes Induced by Chronic Toxoplasma gondii Infection

2017 ◽  
Author(s):  
Ellen Tedford ◽  
Glenn McConkey
Keyword(s):  
Toxoplasma Gondii ◽  
Neurological Diseases ◽  
Behavioral Changes ◽  
Cns Infection ◽  
Parasite Transmission ◽  
Hormonal Responses ◽  
Host Parasite Interactions ◽  
Host Parasite ◽  
Neurological Infection ◽  
Host Brain

Although the parasite Toxoplasma gondii is one of the most pervasive neurotropic pathogens in the world, the host-parasite interactions during CNS infection and consequences of neurological infection are just beginning to be unraveled. The chronic stages of infection have been considered dormant, although several studies have found correlations of infection with an array of host behavioral changes. These may facilitate parasite transmission and impact neurological diseases. During infection, in addition to the presence of the parasites within neurons, host-mediated neuroimmune and hormonal responses to infection are also present. T. gondii induces numerous changes to host neurons during infection and globally alters host neurological signaling pathways, as discussed in this review. Understanding the neurophysiological changes in the host brain is imperative to understanding the parasitic mechanisms and to delineate the effects of this single-celled parasite on health and its contribution to neurological disease.

scholarly journals Toxoplasma gondii PPM3C, a secreted protein phosphatase, affects parasitophorous vacuole effector export

2020 ◽  
Author(s):  
Joshua A. Mayoral ◽  
Tadakimi Tomita ◽  
Vincent Tu ◽  
Jennifer T. Aguilan ◽  
Simone Sidoli ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Parasitophorous Vacuole ◽  
Acute Infection ◽  
Critical Role ◽  
Cell Types ◽  
Effector Proteins ◽  
Secreted Proteins ◽  
Growth Defect ◽  
Label Free

ABSTRACTToxoplasma gondii is a highly successful parasite that infects a significant portion of the human population. As an intracellular parasite, T. gondii thrives within many different cell types due to its residence in the parasitophorous vacuole, a specialized and heavily modified compartment in which parasites divide. Within this vacuole, numerous secreted proteins facilitate functions that optimize intracellular survival. We characterized one such protein, TgPPM3C, which is predicted to contain a domain belonging to the PP2C class of serine/threonine phosphatases and is secreted by both tachyzoites and differentiating bradyzoites into the vacuolar lumen. Genetic deletion of TgPPM3C established that parasites lacking this predicted phosphatase exhibit a minor growth defect in vitro, are avirulent during acute infection in mice, and form fewer cysts in mouse brain during chronic infection. A label-free phosphoproteomic approach was utilized to identify putative TgPPM3C substrates and demonstrated several secreted proteins with altered phosphorylation status in the absence of TgPPM3C. Altered phosphorylation status was seen in MYR1, a protein essential to the process of protein effector export from the parasitophorous vacuole into the host cell, and in GRA16 and GRA28, two exported effector proteins. Defects were seen in the export of GRA16 and GRA28, but not the effector TgIST, in the TgPPM3C knockout strain. Parasites lacking TgPPM3C also exhibited defects in host c-Myc induction, a process influenced by effector export. Phosphomimetic mutations of GRA16 serine residues recapitulated export defects, implicating de-phosphorylation as an important process in facilitating the export of GRA16. These findings provide an example of the emerging critical role that phosphatases play in regulating the complex environment of the T. gondii parasitophorous vacuole.

scholarly journals Expression pattern determines regulatory logic

PLoS ONE ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. e0244864
Author(s):  
Carlos Mora-Martinez
Keyword(s):  
Gene Expression ◽  
Gene Regulatory Networks ◽  
Dna Sequences ◽  
In Silico ◽  
Regulatory Networks ◽  
Expression Patterns ◽  
Cell Types ◽  
Evolutionary Strategy ◽  
Specific Gene ◽  
Gene Regulatory

Large amounts of effort have been invested in trying to understand how a single genome is able to specify the identity of hundreds of cell types. Inspired by some aspects of Caenorhabditis elegans biology, we implemented an in silico evolutionary strategy to produce gene regulatory networks (GRNs) that drive cell-specific gene expression patterns, mimicking the process of terminal cell differentiation. Dynamics of the gene regulatory networks are governed by a thermodynamic model of gene expression, which uses DNA sequences and transcription factor degenerate position weight matrixes as input. In a version of the model, we included chromatin accessibility. Experimentally, it has been determined that cell-specific and broadly expressed genes are regulated differently. In our in silico evolved GRNs, broadly expressed genes are regulated very redundantly and the architecture of their cis-regulatory modules is different, in accordance to what has been found in C. elegans and also in other systems. Finally, we found differences in topological positions in GRNs between these two classes of genes, which help to explain why broadly expressed genes are so resilient to mutations. Overall, our results offer an explanatory hypothesis on why broadly expressed genes are regulated so redundantly compared to cell-specific genes, which can be extrapolated to phenomena such as ChIP-seq HOT regions.

scholarly journals SARS-CoV-2 selectively mimics a cleavable peptide of human ENaC in a strategic hijack of host proteolytic machinery

2020 ◽  
Author(s):  
Praveen Anand ◽  
Arjun Puranik ◽  
Murali Aravamudan ◽  
AJ Venkatakrishnan ◽  
Venky Soundararajan
Keyword(s):  
Cleavage Site ◽  
Molecular Mimicry ◽  
Immune Surveillance ◽  
Cell Types ◽  
Evolutionary Strategy ◽  
Host Proteins ◽  
Α Subunit ◽  
Putative Receptor ◽  
Acid Cleavage ◽  
Cleavable Peptide

Molecular mimicry of host proteins is an evolutionary strategy adopted by viruses to evade immune surveillance and exploit host cell systems. We report that SARS-CoV-2 has evolved a unique S1/S2 cleavage site (RRARSVAS), absent in any previous coronavirus sequenced, that results in mimicry of an identical FURIN-cleavable peptide on the human epithelial sodium channel α-subunit (ENaC-α). Genetic truncation at this ENaC-α cleavage site causes aldosterone dysregulation in patients, highlighting the functional importance of the mimicked SARS-CoV-2 peptide. Single cell RNA-seq from 65 studies shows significant overlap between the expression of ENaC-α and ACE2, the putative receptor for the virus, in cell types linked to the cardiovascular-renal-pulmonary pathophysiology of COVID-19. Triangulating this cellular fingerprint with amino acid cleavage signatures of 178 human proteases shows the potential for tissue-specific proteolytic degeneracy wired into the SARS-CoV-2 lifecycle. We extrapolate that the evolution of SARS-CoV-2 into a global coronavirus pandemic may be in part due to its targeted mimicry of human ENaC and hijack of the associated host proteolytic network.

scholarly journals Quantitative Peptidomics of Mouse Brain After Infection With Cyst-Forming Toxoplasma gondii

2021 ◽  
Vol 12 ◽  
Author(s):  
Chun-Xue Zhou ◽  
Min Gao ◽  
Bing Han ◽  
Hua Cong ◽  
Xing-Quan Zhu ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Behavior Modification ◽  
Label Free ◽  
Obligate Intracellular ◽  
Endogenous Peptides ◽  
Control Brain ◽  
Wide Range ◽  
The Central Nervous System ◽  
And Control ◽  
Host Brain

Toxoplasma gondii is an obligate intracellular parasite capable of establishing persistent infection within the host brain and inducing severe neuropathology. Peptides are important native molecules responsible for a wide range of biological functions within the central nervous system. However, peptidome profiling in host brain during T. gondii infection has never been investigated. Using a label-free peptidomics approach (LC–MS/MS), we identified a total of 2,735 endogenous peptides from acutely infected, chronically infected and control brain samples following T. gondii infection. Quantitative analysis revealed 478 and 344 significantly differentially expressed peptides (DEPs) in the acute and chronic infection stages, respectively. Functional analysis of DEPs by Gene Ontology suggested these DEPs mainly originated from cell part and took part in cellular process. We also identified three novel neuropeptides derived from the precursor protein cholecystokinin. These results demonstrated the usefulness of quantitative peptidomics in determining bioactive peptides and elucidating their functions in the regulation of behavior modification during T. gondii infection.

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