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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性病原体，可在免疫功能低下的患者中引起严重疾病。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感染引起的免疫抑制可导致感染的重新激活。此外，怀孕期间胎儿的感染会导致先天性弓形虫病。某些刚地弓形虫菌株也会在免疫正常的患者中引起严重的眼部疾病。由于缺乏根除慢性感染的有效药物，弓形虫病的治疗面临挑战，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较差，在大量患者中引起过敏反应。迫切需要对弓形虫病进行安全有效的治疗。弓形虫在宿主细胞内复制，并巧妙地操纵宿主细胞，以确保其生存和复制的有利条件。弓形虫感染导致多种宿主信号和代谢途径的差异调节。寄主的许多变化尚不完全清楚，但寄主途径的改变很可能对寄生虫的生长和生存至关重要。类异戊二烯是自然界中种类最丰富的化合物。许多类型的类异戊二烯（如类固醇、胆固醇、类维生素a、类胡萝卜素、泛醌、戊烯基蛋白）是所有生物体细胞机制的重要组成部分，因为它们在各种生物过程中发挥作用。所有的类异戊二烯来源于一个共同的前体，焦磷酸异戊烯基及其异构体焦磷酸二甲基烯基，它们通过甲羟戊酸途径在哺乳动物细胞中合成。人甲羟戊酸途径是他汀类药物和双膦酸盐的药理学靶点，这两种药物在临床上分别用于治疗高胆固醇血症和骨疾病。我们发现，极低剂量的亲脂双膦酸盐和他汀类药物和双膦酸盐的组合，保护小鼠免受致命剂量的弓形虫。体内联合药物（部分用于临床）的协同相互作用，保护小鼠免于死亡，联合指数比体外获得的分数抑制浓度低10倍。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通过抑制抗原呈递细胞中小gtp酶（包括Rab5）的香叶酰化，在小鼠和猴子中具有有效的佐剂活性，导致内体成熟受阻，抗原保留时间延长，T细胞活化增强。此外，抑制甲羟戊酸途径可诱导Th1和细胞溶解性T细胞反应。我们的假设是，他汀类药物和双膦酸盐联合治疗弓形虫感染的有效性涉及免疫系统的参与，并且这种策略可用于对抗其他细胞内病原体的感染。我们将描述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效应中的参与。