Eradicating latent toxoplasmosis

弓形虫是一种温血动物的胞内原生动物寄生虫，已感染 占人类人口的三分之一。复制阶段(速殖子)发展为潜伏期(缓殖子)。 它以包囊的形式存在于宿主细胞内的大脑、心脏和骨骼肌组织中。这些组织囊肿持续存在 在寄主内生活，因为它们不受免疫反应的影响，目前被批准抗寄生虫 药物(如抗叶酸)。组织囊肿可引起免疫受损患者感染的反复再激活 患者，一些研究已经将潜伏性弓形虫病与各种神经疾病联系起来，包括 精神分裂症。该领域最迫切的需求之一是发现拥有 攻击和减少组织囊肿的能力。在最近的研究中，我们证明了愈创木酚(GA)，一种古老的药物 用于治疗高血压，也有强大的抗弓形虫活性，通过其能力 干扰寄生虫的翻译控制。GA已经获得了FDA的批准，可以跨越血脑屏障， 使其成为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，我们发现GA对急性感染的活性不高，但对急性感染的活性显著。 缓虫体组织包囊在隐匿性弓形虫病中，脑囊肿负担比载体剂减轻70-80% 控制。因此，赤霉素A是首批证明有可能降低组织囊肿量的药物之一。 在受感染的动物身上。在无关的研究中，我们的合作者斯通·道格特博士发现类内分泌蛋白 以寄生虫的细胞色素Bc1复合体为靶点的喹诺酮类药物(ELQs)可以减少脑囊肿的负担 ~85%。有趣的是，这两种具有不同作用机制的药物都缺乏充分发挥作用的能力。 根除包囊。我们推测这些残留的包囊是由残留的速殖子形成的，这些速殖子可以被消灭。 通过使用一种药物组合。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，我们将检查特定的大脑区域，以 确定顽固性囊肿残留的位置，并确定其他器官是否含有逃逸的寄生虫。 药物治疗；(Ii)我们将确定GA和ELQ的新组合，或联合给药 抗叶酸，会将组织囊泡减少到检测不到的水平。一种药理策略的鉴定 减少或消除弓形虫组织囊肿将是根治弓形虫疾病的重大进步 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.