Eradicating latent toxoplasmosis

弓形虫是一种寄生于温血动物细胞内的原虫， 三分之一的人口。复制期（速殖子）发育为潜伏期（缓殖子） 在宿主细胞内以包囊的形式存在于脑、心脏和骨骼肌组织中。这些组织囊肿 因为它们不受免疫反应的影响，目前已批准的抗寄生虫药物 药物（如抗叶酸剂）。组织囊肿引起免疫受损患者感染的复发性再激活 一些研究将潜伏性弓形虫病与各种神经系统疾病联系起来，包括 精神分裂症该领域中最迫切的需求之一是发现具有以下性质的化学实体： 攻击和减少组织囊肿的能力。在最近的研究中，我们证明了胍那苄（GA），一种古老的药物， 用于治疗高血压，也具有有效的抗寄生虫活性，通过其能力， 干扰寄生虫翻译控制。GA已经被FDA批准，可以穿过血脑屏障， 这使得它成为一种有吸引力的候选药物，可以重新用作治疗弓形虫病的药物。的小鼠模型中 感染，我们表明GA对急性感染表现出适度的活性，但对 潜伏性弓形虫病中的缓殖子组织包囊，与溶媒相比，脑包囊负荷减少70-80% 对照因此，GA代表了第一批证明有可能降低组织囊肿水平的药物之一 感染的动物。在不相关的研究中，我们的合作者斯通·道吉特博士发现， 靶向寄生虫细胞色素bc 1复合物的喹诺酮类药物（ELQ）可以减少脑囊肿负担， ~ 85%。有趣的是，这两种药物具有不同的作用机制，每种药物都缺乏充分的能力， 根除囊肿我们推测这些残留的包囊是由残余的速殖子引起的， 通过使用药物组合。在这个R21应用程序中，我们建议用两个 具体目标：（i）在用GA或ELQ治疗潜伏感染的小鼠后，我们将检查特定的脑区域， 确定顽固性囊肿的位置，并确定其他器官是否藏有逃避的寄生虫。 （ii）我们将确定是否使用GA和ELQ的新组合，或联合给药 抗叶酸剂，将减少组织囊肿到检测不到的水平。确定一种药理学策略， 减少或消除弓形虫组织囊肿将是根治弓形虫病的一个重大进展。 弓形虫病

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.