Anti-Toxoplasma isoprenoid pathway inhibitors and the host immune response

抗弓形虫类异戊二烯途径抑制剂和宿主免疫反应

基本信息

批准号：
10117182
负责人：
Silvia N Moreno
金额：
$ 22.65万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-02 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10117182
关键词：
AGFG1 gene Adjuvant Allergic Reaction Antigen-Presenting Cells Antigens Biological Process Bone Diseases Cancer Model Carotenoids Category B pathogen Cells Cessation of life Chemotherapy-Oncologic Procedure Cholesterol Clinic Clinical Congenital Toxoplasmosis Cytotoxic T-Lymphocytes Diphosphates Disease Dose Drug usage Effectiveness Fetus Geranyltranstransferase Growth HIV Human Immune response Immune system Immunocompetent Immunocompromised Host Immunologic Adjuvants Immunosuppression In Vitro Infection Investigation Isomerism Lead Mammalian Cell Metabolic Pathway Modeling Modification Monkeys Monomeric GTP-Binding Proteins Mus Nature Neuraxis Organ Transplantation Organism Parasites Pathway interactions Patients Pharmaceutical Preparations Pharmacology Play Pregnancy Protein Isoprenylation Proteins Regulation Retinoids Role Signal Pathway Steroids T cell response T-Cell Activation Testing Therapeutic Effect Time Toxoplasma Toxoplasma gondii Toxoplasmosis Ubiquinone Work acute infection base biodefense bisphosphonate chronic infection design effective therapy farnesyl pyrophosphate geranylgeranyl diphosphate geranylgeranylation hypercholesterolemia in vivo indexing infectious disease chemotherapy inhibitor/antagonist isopentenyl pyrophosphate isoprenoid lipophilicity mevalonate novel strategies novel therapeutic intervention opportunistic pathogen pathogen prenyl prevent protective effect response treatment effect xylulose-5-phosphate

项目摘要

Toxoplasma gondii is an opportunistic pathogen that causes serious disease in immunocompromised patients. Most human infections are asymptomatic but immunosuppression due to organ transplant, cancer chemotherapy, or infection with HIV can lead to re-activation of the infection. In addition, infection of the fetus during pregnancy causes congenital toxoplasmosis. Some strains of T. gondii also cause severe ocular disease in immunocompetent patients. Treatment for toxoplasmosis is challenged by lack of effective drugs to eradicate the chronic infection and as many as 50% of the treated patients do not respond to the therapy. Most of the drugs currently used are poorly distributed to the central nervous system and they trigger allergic reactions in a large number of patients. There is a compelling need for safe and effective treatments for toxoplasmosis. Toxoplasma replicates inside its host cell and masterfully manipulates the host cell to insure favorable conditions for its survival and replication. T. gondii infection results in differential regulation of a variety of host signaling and metabolic pathways. Many of these host changes are not completely understood but it is quite likely that modifications of host pathways are essential for parasite growth and survival. Isoprenoids are the most diverse and abundant compounds occurring in nature. Many types of isoprenoids (e.g. steroids, cholesterol, retinoids, carotenoids, ubiquinones, prenyl proteins) are essential components of the cellular machinery of all organisms due to their roles in a variety of biological processes. All isoprenoids derive from a common precursor, isopentenyl pyrophosphate, and its isomer, dimethylallyl pyrophosphate, which are synthesized in mammalian cells via the mevalonate pathway. The human mevalonate pathway is the pharmacological target of statins and bisphosphonates, drugs used clinically to treat hypercholesterolemia and bone disorders, respectively. We found that very low doses of lipophilic bisphosphonates and combinations of statins and bisphosphonates, protected mice against a lethal dose of Toxoplasma. The synergistic interaction in vivo combining drugs (some used in the clinics), protected mice against death at a combination index 10 times lower than the fractional inhibitory concentration obtained in vitro. Recent work using cancer models revealed that certain statins or bisphosphonates have potent adjuvant activity in mice and monkeys by inhibiting geranylgeranylation of small GTPases, including Rab5, in antigen presenting cells, resulting in arrested endosomal maturation, prolonged antigen retention, and enhanced T cell activation. In addition, inhibiting the mevalonate pathway induces both a Th1 and cytolytic T cell response. Our hypothesis is that the effectiveness of the combination of statins and bisphosphonates for the treatment of T. gondii infection involves the participation of the immune system and that this strategy could be used against infection of other intracellular pathogens. We will characterize the participation of the host immune response in the synergistic effect obtained when combining inhibitors of host and parasite pathways.

弓形虫Gondii是一种机会性病原体，可在免疫组建的患者中引起严重的疾病。大多数人类感染是不对称的，但由于器官移植，癌症化疗或HIV感染引起的免疫抑制可能导致感染的重新激活。此外，怀孕期间的胎儿感染会导致先天性毒质剂。某些弓形虫的菌株还导致免疫能力患者引起严重的眼部疾病。缺乏有效的药物来放射性慢性感染，对弓形虫病的治疗受到挑战，多达50％的治疗患者对治疗没有反应。当前使用的大多数药物分布到中枢神经系统上很差，并且会引发大量患者的过敏反应。对弓形虫病的安全有效疗法的需求迫切有必要。弓形虫在其宿主细胞内复制，并巧妙地操纵宿主细胞，以确保其生存和复制的有利条件。 T. gondii感染会导致各种宿主信号传导和代谢途径的调节。这些宿主变化中的许多尚未完全理解，但是宿主途径的修改对于寄生虫的生长和生存至关重要。类异丙因是自然界中最多样化，最丰富的化合物。由于它们在多种生物学过程中的作用，因此许多类型的类异型（例如类固醇，类固醇，类维生素类动物，类胡萝卜素，泛酮，蛋白质蛋白）是所有生物体的细胞机械的必不可少的成分。所有类异on-源自共同前体，异戊烯基焦磷酸盐及其异构体二甲基二磷酸二甲基二磷酸，它们是通过甲丙酸酯途径在哺乳动物细胞中合成的。人肠甲酸酯途径是他汀类药物和双膦酸盐的药物靶标，分别用于治疗高胆固醇血症和骨骼疾病的药物。我们发现，非常低剂量的亲脂性双膦酸盐以及他汀类药物和双膦酸盐的组合，可保护小鼠免受致命剂量的弓形虫剂量。在体内结合药物（一些在诊所中使用）的协同相互作用，以比在体外获得的分数抑制浓度低10倍的组合指数保护小鼠。最近使用癌症模型的工作表明，某些他汀类药物或双膦酸盐通过抑制抗原呈递细胞在内的小GTPase（包括RAB5）的黄烷基凝聚酰化，在小鼠和猴子中具有可调活性，从而导致了被捕的内体成熟，从而导致延长的抗原延长抗原和增强T细胞活化。另外，抑制甲戊酸途径会影响Th1和细胞溶解T细胞反应。我们的假设是，他汀类药物和双膦酸酯对弓形虫感染的治疗的有效性涉及免疫系统的参与，并且可以将这种策略用于其他细胞内病原体的感染。我们将表征宿主免疫反应在结合宿主和寄生虫途径抑制剂时获得的协同作用的参与。