Neutrophils in the brain are sources of neuroprotective molecules and demonstrate functional heterogeneity during chronic Toxoplasma gondii infection
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PROVIDER: PRJNA868094 | ENA |
REPOSITORIES: ENA
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Project description:Infection with the protozoan parasite Toxoplasma gondii leads to the formation of lifelong cysts in neurons of the brain that can have devastating consequences in the immunocompromised. However, despite the establishment of a chronic inflammatory state and infection-induced neurological changes, there are limited signs of clinical neuropathology resulting in an asymptomatic infection in the immunocompetent. This suggests the work of neuroprotective mechanisms to prevent clinical manifestations of disease. However, such sources of neuroprotection during infection remain largely unknown. This study identifies a population of neutrophils chronically present in the brain during Toxoplasma infection that express the neuroprotective molecules NRG-1, ErbB4, and MSR1. Further phenotyping of this population via flow cytometry and singe-cell RNA sequencing reveals two distinct subsets of neutrophils based on age that display functional heterogeneity. This includes cells transcriptionally prepared to function both as anti-parasitic effector cells and in a more alternative protective manner. Chronic depletion of neutrophils results in increased parasite burden and infection-induced vascular pathology. Lack of neutrophils during chronic infection also deleteriously affects neuronal regeneration and repair mechanisms. In conclusion, this work identifies and demonstrates a functionally diverse chronic neutrophil population that plays a dynamic role in controlling infection outcome in the CNS by balancing classical responses with neuroprotective functions.
2023-12-30 | GSE210883 | GEO
Project description:To increase our understanding of the mechanisms that underlie neuroprotection following glutamate receptor-induced excitotoxicity, we treated primary CD-1 mouse cortical neurons with NMDA in the presence of absence of neuroprotective compounds. The results indicate a convergence at the level of whole genome expression, despite the divergent chemistries and purported mechanisms of action. While more arrays were performed than published, only the extreme arrays were used in subsequent analyses.
2015-01-01 | GSE38701 | GEO
Project description:Toxoplasma gondii is capable of actively invading almost any mammalian cell type including phagocytes. Early events in phagocytic cells such as dendritic cells are not only key to establishing parasite infection, but conversely play a pivotal role in initiating host immunity. It is now recognized that in addition to changes in canonical immune markers and mediators, alteration in metabolism occurs upon activation of phagocytic cells. These metabolic changes are important for supporting the developing immune response, but can affect the availability of nutrients for intracellular pathogens including T. gondii. However, the interaction of T. gondii with these cells and particularly how infection changes their metabolism has not been extensively investigated. Herein, we use a multi-omics approach comprising transcriptomics and metabolomics validated with functional assays to better understand early events in these cells following infection. Analysis of the transcriptome of T. gondii infected bone marrow derived dendritic cells (BMDCs) revealed significant alterations in transcripts associated with cellular metabolism, activation of T cells, inflammation mediated chemokine and cytokine signaling pathways. Multivariant analysis of metabolomic data sets acquired through non-targeted liquid chromatography mass spectroscopy (LCMS) identified metabolites associated with glycolysis, the TCA cycle, oxidative phosphorylation and arginine metabolism as major discriminants between control uninfected and T. gondii infected cells. Consistent with these observations, glucose uptake and lactate dehydrogenase activity were upregulated in T. gondii infected BMDC cultures compared with control BMDCs. Conversely, BMDC mitochondrial membrane potential was reduced in T. gondii-infected cells relative to mitochondria of control BMDCs. These changes to energy metabolism, similar to what has been described following LPS stimulation of BMDCs and macrophages are often termed the Warburg effect. This metabolic reprogramming of cells has been suggested to be an important adaption that provides energy and precursors to facilitate phagocytosis, antigen processing and cytokine production. Other changes to BMDC metabolism are evident following T. gondii infection and include upregulation of arginine degradation concomitant with increased arginase-1 activity and ornithine and proline production. As T. gondii is an arginine auxotroph the resultant reduced cellular arginine levels are likely to curtail parasite multiplication. These results highlight the complex interplay of BMDCs and parasite metabolism within the developing immune response and the consequences for adaptive immunity and pathogen clearance.
| S-EPMC6749083 | biostudies-literature
Project description:Toxoplasma gondii is the causative agent of toxoplasmosis, an infectious disease that affects over 30% of the human world population, causing fatal infections in immunocompromised individuals and neonates. The life cycle of T. gondii is complex, and involves intermediate hosts (birds and mammals) and definitive hosts (felines, including domestic cats). The innate immune repertoire against the parasite involves the production of neutrophil extracellular traps (NET), and neutrophils from several intermediate hosts produce NET induced by T. gondii. However, the mechanisms underlying NET release in response to the parasite have been poorly explored. Therefore, the aims of this study were to investigate whether neutrophils from cats produce NET triggered by T. gondii and to understand the mechanisms thereby involved. Neutrophils from cats were stimulated with T. gondii tachyzoites and NET-derived DNA in the supernatant was quantified during the time. The presence of histone H1 and myeloperoxidase was detected by immunofluorescence. We observed that cat neutrophils produce both classical and rapid/early NET stimulated by T. gondii. Inhibition of elastase, intracellular calcium, and phosphatidylinositol 3-kinase (PI3K)-δ partially blocked classical NET release in response to the parasite. Electron microscopy revealed strands and networks of DNA in close contact or completely entrapping parasites. Live imaging showed that tachyzoites are killed by NET. We conclude that the production of NET is a conserved strategy to control infection by T. gondii amongst intermediate and definitive hosts.
| S-EPMC7716220 | biostudies-literature
Project description: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.
| S-EPMC11246559 | biostudies-literature
Project description:Toxoplasma gondii is an obligate intracellular protozoan parasite that can invade various organs in the host body, including the central nervous system. Chronic intracranial T. gondii is known to be associated with neuroprotection against neurodegenerative diseases through interaction with host brain cells in various ways. The present study investigated the neuroprotective effects of chronic T. gondii infection in mice with cerebral ischemia experimentally produced by middle cerebral artery occlusion (MCAO) surgery. The neurobehavioral effects of cerebral ischemia were assessed by measurement of Garcia score and Rotarod behavior tests. The volume of brain ischemia was measured by triphenyltetrazolium chloride staining. The expression levels of related genes and proteins were determined. After cerebral ischemia, corrected infarction volume was significantly reduced in T. gondii infected mice, and their neurobehavioral function was significantly better than that of the uninfection control group. Chronic T. gondii infection induced the expression of hypoxia-inducible factor 1-alpha (HIF-1α) in the brain before MCAO. T. gondii infection also increased the expression of vascular endothelial growth factor after the cerebral ischemia. It is suggested that chronic intracerebral infection of T. gondii may be a potential preconditioning strategy to reduce neural deficits associated with cerebral ischemia and induce brain ischemic tolerance through the regulation of HIF-1α expression.
| S-EPMC7462801 | biostudies-literature
Project description:Astrocytes differentiate into a spectrum of neurotoxic and neuroprotective reactive subpopulations after CNS injury and in disease. In astrocyte conditional ADCY10 (sAC) knockout mice, reactive astrocytes exhibit a shift towards neurotoxic phenotypes implicating sAC as a critical regulator of neuroprotective astrocyte differentiation.
2023-12-11 | GSE237675 | GEO
Project description:Transcriptome analysis of oocyst, tachyzoite, and bradyzoite development in the type II Toxoplasma gondii strain M4.
| PRJNA147883 | ENA