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Virulence Dec 2023The amoeba parasite is the causative agent of human amebiasis, an enteropathic disease affecting millions of people worldwide. This ancient protozoan is an elementary... (Review)
Review
The amoeba parasite is the causative agent of human amebiasis, an enteropathic disease affecting millions of people worldwide. This ancient protozoan is an elementary example of how parasites evolve with humans, e.g. taking advantage of multiple mechanisms to evade immune responses, interacting with microbiota for nutritional and protective needs, utilizing host resources for growth, division, and encystation. These skills of perpetuate the species and incidence of infection. However, in 10% of infected cases, the parasite turns into a pathogen; the host-parasite equilibrium is then disorganized, and the simple lifecycle based on two cell forms, trophozoites and cysts, becomes unbalanced. Trophozoites acquire a virulent phenotype which, when non-controlled, leads to intestinal invasion with the onset of amoebiasis symptoms. Virulent must cross mucus, epithelium, connective tissue and possibly blood. This highly mobile parasite faces various stresses and a powerful host immune response, with oxidative stress being a challenge for its survival. New emerging research avenues and omics technologies target gene regulation to determine human or parasitic factors activated upon infection, their role in virulence activation, and in pathogenesis; this research bears in mind that is a resident of the complex intestinal ecosystem. The goal is to eradicate amoebiasis from the planet, but the parasitic life of is ancient and complex and will likely continue to evolve with humans. Advances in these topics are summarized here.
Topics: Humans; Entamoeba histolytica; Virulence; Ecosystem; Amebiasis; Intestines
PubMed: 36519347
DOI: 10.1080/21505594.2022.2158656 -
G3 (Bethesda, Md.) Jun 2024In this editorial, Senior Editor Susan Forsburg examines the reasons to keep studying eukaryotic microbes like and —and other yeasts, algae, amoeba, and fungi—even...
In this editorial, Senior Editor Susan Forsburg examines the reasons to keep studying eukaryotic microbes like and —and other yeasts, algae, amoeba, and fungi—even as genetic and genomic technologies now allow manipulation and study of practically any organism. She explores the challenges and opportunities of working in these tiny organisms, pointing to the substantial biology their study has uncovered.
PubMed: 38837137
DOI: 10.1093/g3journal/jkae073 -
The Journal of Cell Biology Sep 2023Phosphoinositide signaling lipids (PIPs) are key regulators of membrane identity and trafficking. Of these, PI(3,5)P2 is one of the least well-understood, despite key...
Phosphoinositide signaling lipids (PIPs) are key regulators of membrane identity and trafficking. Of these, PI(3,5)P2 is one of the least well-understood, despite key roles in many endocytic pathways including phagocytosis and macropinocytosis. PI(3,5)P2 is generated by the phosphoinositide 5-kinase PIKfyve, which is critical for phagosomal digestion and antimicrobial activity. However PI(3,5)P2 dynamics and regulation remain unclear due to lack of reliable reporters. Using the amoeba Dictyostelium discoideum, we identify SnxA as a highly selective PI(3,5)P2-binding protein and characterize its use as a reporter for PI(3,5)P2 in both Dictyostelium and mammalian cells. Using GFP-SnxA, we demonstrate that Dictyostelium phagosomes and macropinosomes accumulate PI(3,5)P2 3 min after engulfment but are then retained differently, indicating pathway-specific regulation. We further find that PIKfyve recruitment and activity are separable and that PIKfyve activation stimulates its own dissociation. SnxA is therefore a new tool for reporting PI(3,5)P2 in live cells that reveals key mechanistic details of the role and regulation of PIKfyve/PI(3,5)P2.
Topics: Animals; Dictyostelium; Endosomes; Mammals; Phagosomes; Phosphatidylinositols; Phosphatidylinositol 3-Kinases
PubMed: 37382666
DOI: 10.1083/jcb.202209077 -
Science Advances Oct 2023Pancreatic ductal adenocarcinoma (PDAC) has a very poor prognosis because of its high propensity to metastasize and its immunosuppressive microenvironment. Using a panel...
Pancreatic ductal adenocarcinoma (PDAC) has a very poor prognosis because of its high propensity to metastasize and its immunosuppressive microenvironment. Using a panel of pancreatic cancer cell lines, three-dimensional (3D) invasion systems, microarray gene signatures, microfluidic devices, mouse models, and intravital imaging, we demonstrate that ROCK-Myosin II activity in PDAC cells supports a transcriptional program conferring amoeboid invasive and immunosuppressive traits and in vivo metastatic abilities. Moreover, we find that immune checkpoint CD73 is highly expressed in amoeboid PDAC cells and drives their invasive, metastatic, and immunomodulatory traits. Mechanistically, CD73 activates RhoA-ROCK-Myosin II downstream of PI3K. Tissue microarrays of human PDAC biopsies combined with bioinformatic analysis reveal that rounded-amoeboid invasive cells with high CD73-ROCK-Myosin II activity and their immunosuppressive microenvironment confer poor prognosis to patients. We propose targeting amoeboid PDAC cells as a therapeutic strategy.
Topics: Animals; Humans; Mice; Adenocarcinoma; Amoeba; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Movement; Cytoskeletal Proteins; Immunosuppression Therapy; Myosin Type II; Pancreatic Neoplasms; Tumor Microenvironment
PubMed: 37851808
DOI: 10.1126/sciadv.adi0244 -
Proceedings of the National Academy of... Aug 2023Cell-to-cell communication is fundamental to multicellular organisms and unicellular organisms living in a microbiome. It is thought to have evolved as a stress- or...
Cell-to-cell communication is fundamental to multicellular organisms and unicellular organisms living in a microbiome. It is thought to have evolved as a stress- or quorum-sensing mechanism in unicellular organisms. A unique cell-to-cell communication mechanism that uses reactive oxygen species (ROS) as a signal (termed the "ROS wave") was identified in flowering plants. This process is essential for systemic signaling and plant acclimation to stress and can spread from a small group of cells to the entire plant within minutes. Whether a similar signaling process is found in other organisms is however unknown. Here, we report that the ROS wave can be found in unicellular algae, amoeba, ferns, mosses, mammalian cells, and isolated hearts. We further show that this process can be triggered in unicellular and multicellular organisms by a local stress or HO treatment and blocked by the application of catalase or NADPH oxidase inhibitors and that in unicellular algae it communicates important stress-response signals between cells. Taken together, our findings suggest that an active process of cell-to-cell ROS signaling, like the ROS wave, evolved before unicellular and multicellular organisms diverged. This mechanism could have communicated an environmental stress signal between cells and coordinated the acclimation response of many different cells living in a community. The finding of a signaling process, like the ROS wave, in mammalian cells further contributes to our understanding of different diseases and could impact the development of drugs that target for example cancer or heart disease.
Topics: Animals; Reactive Oxygen Species; Hydrogen Peroxide; Signal Transduction; Cell Communication; Plants; Mammals
PubMed: 37494396
DOI: 10.1073/pnas.2305496120 -
Biochemical Society Transactions Oct 2023Inorganic polyphosphate (polyP), the polymeric form of phosphate, is attracting ever-growing attention due to the many functions it appears to perform within mammalian... (Review)
Review
Inorganic polyphosphate (polyP), the polymeric form of phosphate, is attracting ever-growing attention due to the many functions it appears to perform within mammalian cells. This essay does not aim to systematically review the copious mammalian polyP literature. Instead, we examined polyP synthesis and functions in various microorganisms and used an evolutionary perspective to theorise key issues of this field and propose solutions. By highlighting the presence of VTC4 in distinct species of very divergent eucaryote clades (Opisthokonta, Viridiplantae, Discoba, and the SAR), we propose that whilst polyP synthesising machinery was present in the ancestral eukaryote, most lineages subsequently lost it during evolution. The analysis of the bacteria-acquired amoeba PPK1 and its unique polyP physiology suggests that eukaryote cells must have developed mechanisms to limit cytosolic polyP accumulation. We reviewed the literature on polyP in the mitochondria from the perspective of its endosymbiotic origin from bacteria, highlighting how mitochondria could possess a polyP physiology reminiscent of their 'bacterial' beginning that is not yet investigated. Finally, we emphasised the similarities that the anionic polyP shares with the better-understood negatively charged polymers DNA and RNA, postulating that the nucleus offers an ideal environment where polyP physiology might thrive.
Topics: Animals; Polyphosphates; Mammals; Eukaryotic Cells; Mitochondria; Biology
PubMed: 37844192
DOI: 10.1042/BST20230483