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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.

刚地弓形虫是一种机会致病菌，可导致免疫功能低下患者患上严重疾病。大多数人类感染是无症状的，但由于器官移植、癌症化疗或HIV感染而导致的免疫抑制可导致感染的重新激活。此外，怀孕期间胎儿感染弓形虫会导致先天性弓形虫病。一些菌株的T.弓形虫还在免疫功能正常的患者中引起严重的眼部疾病。弓形虫病的治疗受到缺乏根除慢性感染的有效药物的挑战，多达50%的治疗患者对治疗没有反应。目前使用的大多数药物在中枢神经系统的分布很差，它们在大量患者中引发过敏反应。迫切需要安全有效的弓形虫病治疗方法。弓形虫在其宿主细胞内复制，并熟练地操纵宿主细胞以确保其生存和复制的有利条件。T.弓形虫感染导致多种宿主信号传导和代谢途径的不同调节。许多这些主机的变化并不完全理解，但它是很可能的主机途径的修改是必不可少的寄生虫的生长和生存。类异戊二烯是自然界中存在的最多样和最丰富的化合物。许多类型的类异戊二烯（例如类固醇、胆固醇、类视色素、类胡萝卜素、泛醌、异戊烯基蛋白）由于它们在各种生物过程中的作用而成为所有生物体的细胞机器的必需组分。所有类异戊二烯都来源于一个共同的前体异戊烯基焦磷酸及其异构体二甲基烯丙基焦磷酸，它们在哺乳动物细胞中通过甲羟戊酸途径合成。人甲羟戊酸途径是他汀类药物和双膦酸盐药物的药理学靶点，这两种药物分别在临床上用于治疗高胆固醇血症和骨疾病。我们发现，非常低剂量的亲脂性双膦酸盐和他汀类药物和双膦酸盐的组合，保护小鼠免受致死剂量的弓形虫。体内协同相互作用结合药物（一些用于临床），保护小鼠免于死亡的组合指数低于10倍，在体外获得的部分抑制浓度。最近使用癌症模型的研究表明，某些他汀类药物或双膦酸盐在小鼠和猴中具有有效的佐剂活性，通过抑制抗原呈递细胞中小GTP酶（包括Rab5）的香叶基香叶基化，导致内体成熟停滞，延长抗原保留和增强T细胞活化。此外，抑制甲羟戊酸途径诱导Th1和细胞溶解性T细胞应答。我们的假设是，他汀类药物和双膦酸盐联合治疗T。弓形虫感染涉及免疫系统的参与，这种策略可用于对抗其他细胞内病原体的感染。我们将表征当结合宿主和寄生虫途径的抑制剂时获得的协同效应中宿主免疫应答的参与。