Eradicating latent toxoplasmosis

根除潜伏弓形虫病

基本信息

批准号：
10116280
负责人：
William J Sullivan
金额：
$ 22.95万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
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：
2020-03-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10116280
关键词：
Accounting Acute Acute Disease Address Animals Antiparasitic Agents Back Biological Assay Blood Blood - brain barrier anatomy Brain Brain region Cells Chemicals Chronic Clinical Combined Modality Therapy Confusion Cyst Cytochrome bc1 Complex Disease Disease remission Drug Combinations Drug usage FDA approved Folic Acid Antagonists Goals Guanabenz Headache Human Hypertension Immune Immune response Immune system Immunoblotting Immunocompromised Host Inbred BALB C Mice Infection Life Life Cycle Stages Monitor Mus Muscle Myocardium Neurologic Symptoms Organ Parasites Patients Pharmaceutical Preparations Pharmacology Pharmacotherapy Population Predatory Behavior Proliferating Pyrimethamine Quinolones Recurrence Research Residual state Schizophrenia Seeds Seizures Skeletal Muscle Source Sulfadiazine Testing Tissues Toxoplasma Toxoplasma gondii Toxoplasmosis acute infection immunosuppressed infant infection mouse model nervous system disorder novel novel therapeutics pathogen recurrent infection transmission process

项目摘要

Toxoplasma gondii is an intracellular protozoan parasite of warm-blooded animals, and has infected up to one-third of the human population. The replicative stage (tachyzoite) develops into a latent stage (bradyzoite) that resides inside host cells as cysts in brain, heart, and skeletal muscle tissues. These tissue cysts persist within the host for life, as they are impervious to the immune response and currently approved anti-parasitic drugs (e.g. antifolates). Tissue cysts give rise to recurrent reactivation of infection in immune compromised patients, and some studies have correlated latent toxoplasmosis with various neurological disorders, including schizophrenia. One of the most pressing needs in the field is the discovery of chemical entities possessing the ability to attack and reduce tissue cysts. In recent studies, we demonstrated that guanabenz (GA), an old drug used to treat hypertension, also has potent anti-parasitic activity against Toxoplasma through its ability to interfere with parasite translational control. GA is already FDA-approved and can cross the blood-brain barrier, making it an attractive candidate for repurposing as a drug to treat toxoplasmosis. In a mouse model of infection, we showed that GA displayed modest activity against acute infection, but remarkable activity against bradyzoite tissue cysts in latent toxoplasmosis, reducing the brain cyst burden 70-80% compared to vehicle controls. GA thus represents one of the first drugs that demonstrates it is possible to reduce tissue cyst levels in infected animals. In unrelated studies, our collaborator, Dr. Stone Doggett, found that endochin-like quinolones (ELQs), which target the parasite's cytochrome bc1 complex, can reduce brain cyst burden up to ~85%. Intriguingly, these two drugs, which have differing mechanisms of action, each lacks the ability to fully eradicate cysts. We hypothesize that these remaining cysts arise from residual tachyzoites that can be nullified through the use of a drug combination. In this R21 application, we propose to address this hypothesis with two specific aims: (i) after treating latently infected mice with GA or ELQ, we will examine specific brain regions to determine where the intractable cysts remain, and determine whether other organs harbor parasites that evade drug treatment; (ii) we will determine whether novel combinations of GA and ELQ, or co-administration of antifolates, will reduce tissue cysts to undetectable levels. The identification of a pharmacological strategy that reduces or eliminates Toxoplasma tissue cysts would be a significant advance towards a radical cure for toxoplasmosis.

弓形虫是温血动物的细胞内原生动物寄生虫，已感染多达人口的三分之一。复制阶段（速殖子）发展为潜伏阶段（缓殖子）它以脑、心脏和骨骼肌组织中的囊肿形式存在于宿主细胞内。这些组织囊肿持续存在终生在宿主体内，因为它们不受免疫反应的影响，并且目前已批准抗寄生虫药物（例如抗叶酸剂）。组织囊肿会导致免疫受损的感染反复重新激活患者，一些研究已将潜伏性弓形虫病与各种神经系统疾病相关，包括精神分裂症。该领域最紧迫的需求之一是发现具有以下特性的化学实体：攻击和减少组织囊肿的能力。在最近的研究中，我们证明了瓜那苯（GA）这种老药用于治疗高血压，还具有有效的抗弓形虫活性干扰寄生虫的翻译控制。 GA已获得FDA批准，可以穿过血脑屏障，使其成为重新用作治疗弓形虫病的药物的有吸引力的候选者。在小鼠模型中感染时，我们发现 GA 对急性感染表现出适度的活性，但对潜伏性弓形体病中的缓殖子组织囊肿，与媒介物相比，脑囊肿负担减少 70-80% 控制。因此，GA 是最早证明可以降低组织囊肿水平的药物之一在受感染的动物中。在不相关的研究中，我们的合作者 Stone Doggett 博士发现，内啡肽样喹诺酮类药物 (ELQ) 靶向寄生虫的细胞色素 bc1 复合物，可减少脑囊肿负担〜85％。有趣的是，这两种药物具有不同的作用机制，但各自都缺乏充分发挥作用的能力。根除囊肿。我们假设这些剩余的包囊来自残留的速殖子，可以将其消除通过使用药物组合。在这个 R21 应用程序中，我们建议用两个方法来解决这个假设具体目标：（i）用 GA 或 ELQ 治疗潜伏感染小鼠后，我们将检查特定的大脑区域以确定顽固性包囊残留的位置，并确定其他器官是否含有逃避的寄生虫药物治疗； (ii) 我们将确定是否采用 GA 和 ELQ 的新组合，或联合给药抗叶酸剂，会将组织囊肿减少到不可检测的水平。药理学策略的确定减少或消除弓形虫组织囊肿将是彻底治愈弓形虫的重大进步弓形体病。