A5022658497- Toxoplasma gondii Research Studies
- Herpesvirus Infections and Treatments
- Autophagy in Disease and Therapy
- Cytomegalovirus and herpesvirus research
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Mosquito-borne diseases and control
- Immune Response and Inflammation
- Parasitic Infections and Diagnostics
- Plant and Fungal Interactions Research
- Polyamine Metabolism and Applications
- Mitochondrial Function and Pathology
- Immune cells in cancer
- Virus-based gene therapy research
- ATP Synthase and ATPases Research
- Legionella and Acanthamoeba research
- Rabies epidemiology and control
- Research on Leishmaniasis Studies
- Fungal and yeast genetics research
- Antifungal resistance and susceptibility
- Vitamin C and Antioxidants Research
- Heme Oxygenase-1 and Carbon Monoxide
- Genomics, phytochemicals, and oxidative stress
- interferon and immune responses
- Paraquat toxicity studies and treatments
- Poxvirus research and outbreaks
University of Michigan
2015-2025
WaterNSW
2021
Toxoplasma gondii is a widely distributed protozoan pathogen that causes devastating ocular and central nervous system disease. We show the endochin-like quinolone (ELQ) class of compounds contains extremely potent inhibitors T. growth in vitro effective against acute latent toxoplasmosis mice. screened 50 ELQs selected two lead compounds, ELQ-271 ELQ-316, for evaluation. have IC values 0.1 nM 0.007 nM, respectively. ELQ-316 ED 0.14 mg/kg 0.08 when administered orally to mice with...
New therapies are needed for the treatment of toxoplasmosis, which is a disease caused by protozoan parasite Toxoplasma gondii. To this end, we previously developed potent and selective inhibitor (compound 1) gondii calcium-dependent protein kinase 1 (TgCDPK1) that possesses antitoxoplasmosis activity in vitro vivo. Unfortunately, has human ether-a-go-go-related gene (hERG) inhibitory activity, associated with long Q-T syndrome, consequently presents cardiotoxicity risk. Here, describe...
ABSTRACT Macroautophagy is an important cellular process involving lysosomal degradation of cytoplasmic components, facilitated by autophagy-related proteins. In the protozoan parasite Toxoplasma gondii , autophagy has been demonstrated to play a key role in adapting stress and persistence chronic infection. Despite limited knowledge about core machinery T. two PROPPIN family proteins (TgPROP1 TgPROP2) have identified with homology Atg18/WIPI. Prior research acute-stage tachyzoites suggests...
Many of the world’s warm-blooded species are chronically infected with Toxoplasma gondii tissue cysts, including an estimated one-third global human population. The cellular processes that permit long-term persistence within cyst largely unknown for T. and related coccidian parasites impact animal health. Herein, we show genetic ablation TgATG9 substantially reduces canonical autophagy compromises bradyzoite viability. Transmission electron microscopy revealed numerous structural...
Macrophage metabolic plasticity is central to inflammatory programming, yet mechanisms of coordinating and programs during infection are poorly defined. Here, we show that type I interferon (IFN) temporally guides control inflammation methicillin-resistant Staphylococcus aureus (MRSA) infection. We find staggered Toll-like receptor IFN signaling in macrophages permit a transient energetic state combined oxidative phosphorylation (OXPHOS) aerobic glycolysis followed by inducible nitric oxide...
Toxoplasmosis continues to be a public health problem, causing significant morbidity worldwide. Currently available medications, effective for acute toxoplasmosis, are nonetheless problematic due adverse side effects in many patients. In addition, no medication is able completely eradicate the parasite cysts, rendering infected individuals at risk reactivation upon becoming immunocompromised. We examined anti–T. gondii activity of 2 derivatives artemisinin. vitro metabolic stability tests...
Toxoplasmosis is a potentially fatal infection for immunocompromised people and the developing fetus. Current medicines toxoplasmosis have high rates of adverse effects that interfere with therapeutic prophylactic regimens. Endochin-like quinolones (ELQs) are potent inhibitors Toxoplasma gondii proliferation in vitro animal models acute latent infection. ELQ-316, particular, was found to be effective orally against mice highly selective T. cytochrome b over human .
Acute virulence in Toxoplasma gondii is linked to an excessive proinflammatory cytokine cascade during laboratory murine infection. Previous work showed that T. secretes a pore forming protein, PLP1, required for efficient cytolytic egress from host cells. Deletion of the PLP1 gene results defective infected culture cells and marked reduction parasite virulence. The goal present study was gain insight into nature attenuated observed knockout compared wild type (WT) RH parasites. Using vivo...
The mammalian endoplasmic reticulum (ER) stress sensor inositol-requiring enzyme 1α (IRE1α) is essential for cellular homeostasis and plays key roles in infection responses, including innate immunity microbicidal activity. While IRE1α functions through the IRE1α-XBP1S axis are known, its XBP1S-independent less well understood, during fungal still emerging. We demonstrate that Candida albicans activates macrophage via C-type lectin receptor signaling independent of protein misfolding,...
Abstract The parasite Toxoplasma gondii persists in its hosts by converting from replicating tachyzoites to latent bradyzoites housed tissue cysts. molecular mechanisms that mediate T. differentiation remain poorly understood. Through a mutagenesis screen, we identified translation initiation factor eIF1.2 as critical for differentiation. A F97L mutation or the genetic ablation of (∆ eif1.2 ) markedly impeded bradyzoite cyst formation vitro and vivo. We demonstrated, at single-molecule...
Individuals chronically infected with the intracellular parasite Toxoplasma gondii are at risk of experiencing reactivated disease that can result in progressive loss vision. No effective treatments exist for chronic toxoplasmosis due part to a poor understanding biology underlying infection and lack well-validated potential targets. We show here T. transporter is functionally linked protein digestion within lysosome-like organelle this necessary sustain culture experimentally mice. Ablating...
Activation of the endoplasmic reticulum stress sensor, IRE1α, is required for effective immune responses against bacterial infection and associated with human inflammatory diseases in which neutrophils are a key component. However, specific role IRE1α regulating neutrophil effector function has not been studied. In this study, we show that infection-induced activation licenses antimicrobial capacity, including IL-1β production, formation extracellular traps (NETs), methicillin-resistant...
Chronic neurologic infection with Toxoplasma gondii is relatively common in humans and one of the strongest known risk factors for schizophrenia. Nevertheless, exact neuropathological mechanisms linking T schizophrenia remain unclear. Here we utilize a mouse model chronic to identify protein biomarkers that are altered serum brain samples at 2 time points during infection. Furthermore, compare identified those differing between "postmortem" from 35 patients 33 healthy controls. Our findings...
Toxoplasma gondii is a protozoan parasite that persists in the central nervous system as intracellular chronic-stage bradyzoites are encapsulated by thick cyst wall. While wall separates from host cytosol, it has been posited small solutes can traverse to sustain bradyzoites. Recently, was found cytosolic macromolecules cross parasitophorous vacuole and ingested digested actively replicating acute-stage tachyzoites. However, extent which have an active ingestion pathway remained unknown. To...
is a protozoan parasite that infects broad spectrum of hosts and can colonize many organs cell types. The ability to reside within wide range different niches requires substantial adaptability diverse microenvironments. Very little known about how this senses various milieus adapts its metabolism survive, replicate during the acute stage, then differentiate chronic stage.
Abstract Toxoplasma gondii is a protozoan parasite that infects broad spectrum of hosts and can colonize many organs cell types. The ability to reside within wide range different niches requires substantial adaptability diverse microenvironments. Very little known about how this senses various milieus adapts its metabolism survive, replicate during the acute stage, then differentiate chronic stage. Most eukaryotes, from yeast mammals, rely on nutrient sensing machinery involving TORC complex...
Abstracts The parasite Toxoplasma gondii persists in its hosts by converting from replicating tachyzoites to latent bradyzoites housed tissue cysts. molecular mechanisms that mediate T. differentiation remain poorly understood. Through a mutagenesis screen, we identified translation initiation factor eIF1.2 as critical for differentiation. A F97L mutation or the genetic ablation of (Δ eif1.2 ) markedly impeded bradyzoite cyst formation vitro and vivo . We demonstrated, at single-molecule...
Fine-tuned inflammation during infection enables pathogen clearance while minimizing host damage. Inflammation regulation depends on macrophage metabolic plasticity, yet coordination of and inflammatory programs is underappreciated. Here we show that type I interferon (IFN) temporally guides control methicillin-resistant Staphylococcus aureus (MRSA) infection. In macrophages, staggered Toll-like receptor IFN signaling permitted a transient respiratory burst followed by inducible nitric oxide...
Macroautophagy is an important cellular process involving lysosomal degradation of cytoplasmic components, facilitated by autophagy-related proteins (ATGs). In the protozoan parasite Toxoplasma gondii , autophagy has been demonstrated to play a key role in adapting stress and persistence chronic infection. Despite limited knowledge about core machinery T. two PROPPIN family (TgPROP1 TgPROP2) have identified with homology Atg18/WIPI. Prior research acute stage tachyzoites suggests that...