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Journal of Fungi (Basel, Switzerland) Jul 2023Microsporidia are a large group of mysterious obligate intracellular eukaryotic parasites. The microsporidian spore can survive in the absence of nutrients for years... (Review)
Review
Microsporidia are a large group of mysterious obligate intracellular eukaryotic parasites. The microsporidian spore can survive in the absence of nutrients for years under harsh conditions and germinate within seconds under the stimulation of environmental changes like pH and ions. During germination, microsporidia experience an increase in intrasporal osmotic pressure, which leads to an influx of water into the spore, followed by swelling of the polaroplasts and posterior vacuole, which eventually fires the polar filament (PF). Infectious sporoplasm was transported through the extruded polar tube (PT) and delivered into the host cell. Despite much that has been learned about the germination of microsporidia, there are still several major questions that remain unanswered, including: (i) There is still a lack of knowledge about the signaling pathways involved in spore germination. (ii) The germination of spores is not well understood in terms of its specific energetics. (iii) Limited understanding of how spores germinate and how the nucleus and membranes are rearranged during germination. (iv) Only a few proteins in the invasion organelles have been identified; many more are likely undiscovered. This review summarizes the major resolved and unresolved issues concerning the process of microsporidian spore germination.
PubMed: 37504762
DOI: 10.3390/jof9070774 -
Acta Neuropathologica Nov 2023Central serous chorioretinopathy (CSCR) belongs to the pachychoroid spectrum, a pathological phenotype of the choroidal vasculature, in which blood flow is under the...
Central serous chorioretinopathy (CSCR) belongs to the pachychoroid spectrum, a pathological phenotype of the choroidal vasculature, in which blood flow is under the choroidal nervous system (ChNS) regulation. The pathogenesis of CSCR is multifactorial, with the most recognised risk factor being intake of glucocorticoids, which activate both the gluco- and the mineralocorticoid (MR) receptors. As MR over-activation is pathogenic in the retina and choroid, it could mediate the pathogenic effects of glucocorticoids in CSCR. But the role of MR signalling in pachychoroid is unknown and whether it affects the ChNS has not been explored. Using anatomo-neurochemical characterisation of the ChNS in rodents and humans, we discovered that beside innervation of arteries, choroidal veins and choriocapillaris are also innervated, suggesting that the entire choroidal vasculature is under neural control. The numerous synapses together with calcitonin gene-related peptide (CGRP) vesicles juxtaposed to choroidal macrophages indicate a neuro-immune crosstalk. Using ultrastructural approaches, we show that transgenic mice overexpressing human MR, display a pachychoroid-like phenotype, with signs of choroidal neuropathy including myelin abnormalities, accumulation and enlargement of mitochondria and nerves vacuolization. Transcriptomic analysis of the RPE/choroid complex in the transgenic mice reveals regulation of corticoids target genes, known to intervene in nerve pathophysiology, such as Lcn2, rdas1/dexras1, S100a8 and S100a9, rabphilin 3a (Rph3a), secretogranin (Scg2) and Kinesin Family Member 5A (Kif5a). Genes belonging to pathways related to vasculature development, hypoxia, epithelial cell apoptosis, epithelial mesenchymal transition, and inflammation, support the pachychoroid phenotype and highlight downstream molecular targets. Hypotheses on the imaging phenotype of pachychoroid in humans are put forward in the light of these new data. Our results provide evidence that MR overactivation causes a choroidal neuropathy that could explain the pachychoroid phenotype found in transgenic mice overexpressing human MR. In patients with pachychoroid and CSCR in which systemic dysautonomia has been demonstrated, MR-induced choroidal neuropathy could be the missing link between corticoids and pachychoroid.
Topics: Animals; Mice; Humans; Receptors, Mineralocorticoid; Tomography, Optical Coherence; Choroid; Adrenal Cortex Hormones; Glucocorticoids; Nervous System; Mice, Transgenic; Retrospective Studies
PubMed: 37682293
DOI: 10.1007/s00401-023-02628-3 -
BioRxiv : the Preprint Server For... Nov 2023Sialidosis is a glycoprotein storage disease caused by deficiency of the lysosomal sialidase NEU1, which leads to pathogenic accumulation of sialylated glycoproteins and...
Sialidosis is a glycoprotein storage disease caused by deficiency of the lysosomal sialidase NEU1, which leads to pathogenic accumulation of sialylated glycoproteins and oligosaccharides in tissues and body fluids. The disease belongs to the group of orphan disorders with no therapy currently available. Here, we have tested the therapeutic potential of AAV-mediated gene therapy for the treatment of sialidosis in a mouse model of the disease. One-month-old mice were co-injected with two scAAV2/8 vectors, expressing NEU1 and its chaperone PPCA, and sacrificed at 3 months post-injection. Treated mice were phenotypically indistinguishable from their WT controls. Histopathologically, they showed diminished or absent vacuolization in cells of visceral organs, including the kidney, as well as the choroid plexus and other areas of the brain. This was accompanied by restoration of NEU1 activity in most tissues, reversal of sialyl-oligosacchariduria, and normalization of lysosomal exocytosis in the CSF and serum of treated mice. AAV injection prevented the occurrence of generalized fibrosis, which is a prominent contributor of disease pathogenesis in mice and likely in patients. Overall, this therapeutic strategy holds promise for the treatment of sialidosis and may be applicable to adult forms of human idiopathic fibrosis with low NEU1 expression.
PubMed: 38014061
DOI: 10.1101/2023.11.10.566667 -
PLoS Pathogens Jul 2023L. pneumophila propagates in eukaryotic cells within a specialized niche, the Legionella-containing vacuole (LCV). The infection process is controlled by over 330...
L. pneumophila propagates in eukaryotic cells within a specialized niche, the Legionella-containing vacuole (LCV). The infection process is controlled by over 330 effector proteins delivered through the type IV secretion system. In this study, we report that the Legionella MavH effector localizes to endosomes and remodels host actin cytoskeleton in a phosphatidylinositol 3-phosphate (PI(3)P) dependent manner when ectopically expressed. We show that MavH recruits host actin capping protein (CP) and actin to the endosome via its CP-interacting (CPI) motif and WH2-like actin-binding domain, respectively. In vitro assays revealed that MavH stimulates actin assembly on PI(3)P-containing liposomes causing their tubulation. In addition, the recruitment of CP by MavH negatively regulates F-actin density at the membrane. We further show that, in L. pneumophila-infected cells, MavH appears around the LCV at the very early stage of infection and facilitates bacterium entry into the host. Together, our results reveal a novel mechanism of membrane tubulation induced by membrane-dependent actin polymerization catalyzed by MavH that contributes to the early stage of L. pneumophila infection by regulating host actin dynamics.
Topics: Legionella pneumophila; Actins; Polymerization; Phosphatidylinositol Phosphates; Vacuoles; Bacterial Proteins
PubMed: 37463171
DOI: 10.1371/journal.ppat.1011512 -
Pathogens (Basel, Switzerland) Feb 2024The malaria parasite resides within erythrocytes during one stage of its life cycle. During this intraerythrocytic period, the parasite ingests the erythrocyte cytoplasm... (Review)
Review
The malaria parasite resides within erythrocytes during one stage of its life cycle. During this intraerythrocytic period, the parasite ingests the erythrocyte cytoplasm and digests approximately two-thirds of the host cell hemoglobin. This digestion occurs within a lysosome-like organelle called the digestive vacuole. Several proteases are localized to the digestive vacuole and these proteases sequentially breakdown hemoglobin into small peptides, dipeptides, and amino acids. The peptides are exported into the host cytoplasm via the chloroquine-resistance transporter and an amino acid transporter has also been identified on the digestive vacuole membrane. The environment of the digestive vacuole also provides appropriate conditions for the biocrystallization of toxic heme into non-toxic hemozoin by a poorly understood process. Hemozoin formation is an attribute of and and is not exhibited by other intraerythrocytic protozoan parasites. The efficient degradation of hemoglobin and detoxification of heme likely plays a major role in the high level of replication exhibited by malaria parasites within erythrocytes. Unique features of the digestive vacuole and the critical importance of nutrient acquisition provide therapeutic targets for the treatment of malaria.
PubMed: 38535526
DOI: 10.3390/pathogens13030182 -
The Journal of Antimicrobial... Oct 2023Pyronaridine-artesunate was recently strongly recommended in the 2022 update of the WHO Guidelines for the Treatment of Malaria, becoming the newest artemisinin-based... (Review)
Review
Pyronaridine-artesunate was recently strongly recommended in the 2022 update of the WHO Guidelines for the Treatment of Malaria, becoming the newest artemisinin-based combination therapy (ACT) for both uncomplicated Plasmodium falciparum and Plasmodium vivax malaria. Pyronaridine-artesunate, available as a tablet and paediatric granule formulations, is being adopted in regions where malaria treatment outcome is challenged by increasing chloroquine resistance. Pyronaridine is an old antimalarial agent that has been used for more than 50 years as a blood schizonticide, which exerts its antimalarial activity by interfering with the synthesis of the haemozoin pigment within the Plasmodium digestive vacuole. Pyronaridine exhibits a high blood-to-plasma distribution ratio due to its tendency to accumulate in blood cells. This feature is believed to play a crucial role in its pharmacokinetic (PK) properties and pharmacological activity. The PK characteristics of pyronaridine include rapid oral absorption, large volumes of distribution and low total body clearance, resulting in a long terminal apparent half-life. Moreover, differences in PK profiles have been observed between healthy volunteers and malaria-infected patients, indicating a potential disease-related impact on PK properties. Despite a long history, there is only limited knowledge of the clinical PK and pharmacodynamics of pyronaridine, particularly in special populations such as children and pregnant women. We here provide a comprehensive overview of the clinical pharmacology of pyronaridine in the treatment of malaria.
Topics: Pregnancy; Humans; Child; Female; Malaria, Falciparum; Antimalarials; Malaria; Naphthyridines; Chloroquine
PubMed: 37638690
DOI: 10.1093/jac/dkad260 -
Moschus ameliorates glutamate-induced cellular damage by regulating autophagy and apoptosis pathway.Scientific Reports Oct 2023Alzheimer's disease (AD), a neurodegenerative disorder, causes short-term memory and cognition declines. It is estimated that one in three elderly people die from AD or...
Alzheimer's disease (AD), a neurodegenerative disorder, causes short-term memory and cognition declines. It is estimated that one in three elderly people die from AD or other dementias. Chinese herbal medicine as a potential drug for treating AD has gained growing interest from many researchers. Moschus, a rare and valuable traditional Chinese animal medicine, was originally documented in Shennong Ben Cao Jing and recognized for its properties of reviving consciousness/resuscitation. Additionally, Moschus has the efficacy of "regulation of menstruation with blood activation, relief of swelling and pain" and is used for treating unconsciousness, stroke, coma, and cerebrovascular diseases. However, it is uncertain whether Moschus has any protective effect on AD patients. We explored whether Moschus could protect glutamate (Glu)-induced PC12 cells from cellular injury and preliminarily explored their related action mechanisms. The chemical compounds of Moschus were analyzed and identified by GC-MS. The Glu-induced differentiated PC12 cell model was thought to be the common AD cellular model. The study aims to preliminarily investigate the intervention effect of Moschus on Glu-induced PC12 cell damage as well as their related action mechanisms. Cell viability, lactate dehydrogenase (LDH), mitochondrial reactive oxygen species, mitochondrial membrane potential (MMP), cell apoptosis, autophagic vacuoles, autolysosomes or autophagosomes, proteins related to apoptosis, and the proteins related to autophagy were examined and analyzed. Seventeen active compounds of the Moschus sample were identified based on GC-MS analysis. In comparison to the control group, Glu stimulation increased cell viability loss, LDH release, mitochondrial damage, loss of MMP, apoptosis rate, and the number of cells containing autophagic vacuoles, and autolysosomes or autophagosomes, while these results were decreased after the pretreatment with Moschus and 3-methyladenine (3-MA). Furthermore, Glu stimulation significantly increased cleaved caspase-3, Beclin1, and LC3II protein expression, and reduced B-cell lymphoma 2/BAX ratio and p62 protein expression, but these results were reversed after pretreatment of Moschus and 3-MA. Moschus has protective activity in Glu-induced PC12 cell injury, and the potential mechanism might involve the regulation of autophagy and apoptosis. Our study may promote research on Moschus in the field of neurodegenerative diseases, and Moschus may be considered as a potential therapeutic agent for AD.
Topics: Animals; Rats; Female; Humans; Aged; Glutamic Acid; Autophagy; Reactive Oxygen Species; Autophagosomes; Apoptosis; Alzheimer Disease; PC12 Cells; Cell Survival
PubMed: 37903904
DOI: 10.1038/s41598-023-45878-7 -
Microbiology (Reading, England) Nov 2023is an obligate intracellular pathogenic bacterium that causes heartwater, a fatal disease of ruminants in tropical areas. Some human cases have also been reported. This... (Review)
Review
is an obligate intracellular pathogenic bacterium that causes heartwater, a fatal disease of ruminants in tropical areas. Some human cases have also been reported. This globally important pathogen is primarily transmitted by ticks of the genus and threatens American mainland. replicates within eukaryotic mammal or tick cell is a membrane-bound vacuole, where it undergoes a biphasic developmental growth cycle and differentiates from noninfectious replicative form into infectious elementary bodies. The ability of to hijack host cellular processes and avoid innate immunity is a fundamental, but not yet fully understood, virulence trait of this stealth pathogen in the genomic era.
Topics: Ehrlichia ruminantium
PubMed: 37994906
DOI: 10.1099/mic.0.001415 -
Plant Biotechnology Journal Nov 2023Large amounts of potash fertilizer are often applied to apple (Malus domestica) orchards to enhance fruit quality and yields, but this treatment aggravates KCl-based...
Large amounts of potash fertilizer are often applied to apple (Malus domestica) orchards to enhance fruit quality and yields, but this treatment aggravates KCl-based salinity stress. Melatonin (MT) is involved in a variety of abiotic stress responses in plants. However, its role in KCl stress tolerance is still unknown. In the present study, we determined that an appropriate concentration (100 μm) of MT significantly alleviated KCl stress in Malus hupehensis by enhancing K efflux out of cells and compartmentalizing K in vacuoles. Transcriptome deep-sequencing analysis identified the core transcription factor gene MdWRKY53, whose expression responded to both KCl and MT treatment. Overexpressing MdWRKY53 enhanced KCl tolerance in transgenic apple plants by increasing K efflux and K compartmentalization. Subsequently, we characterized the transporter genes MdGORK1 and MdNHX2 as downstream targets of MdWRKY53 by ChIP-seq. MdGORK1 localized to the plasma membrane and enhanced K efflux to increase KCl tolerance in transgenic apple plants. Moreover, overexpressing MdNHX2 enhanced the KCl tolerance of transgenic apple plants/callus by compartmentalizing K into the vacuole. RT-qPCR and LUC activity analyses indicated that MdWRKY53 binds to the promoters of MdGORK1 and MdNHX2 and induces their transcription. Taken together, our findings reveal that the MT-WRKY53-GORK1/NHX2-K module regulates K homeostasis to enhance KCl stress tolerance in apple. These findings shed light on the molecular mechanism of apple response to KCl-based salinity stress and lay the foundation for the practical application of MT in salt stress.
Topics: Melatonin; Malus; Salt Tolerance; Homeostasis; Stress, Physiological; Gene Expression Regulation, Plant; Plant Proteins; Plants, Genetically Modified
PubMed: 37465981
DOI: 10.1111/pbi.14129