Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
mBio. 2019 Apr 30;10(2):e00381-19. doi: 10.1128/mBio.00381-19.
is an intracellular parasite that has infected one-third of humans. The infection is permanent because the replicative form (tachyzoite) converts into a latent tissue cyst form (bradyzoite) that evades host immunity and is impervious to current drugs. The continued presence of these parasitic cysts hinders treatment and leads to chronic infection that has been linked to behavioral changes in rodents and neurological disease in humans. How these behavioral changes occur, and whether they are due to parasite manipulation or the host response to infection, remains an outstanding question. We previously showed that guanabenz possesses antiparasitic activity; here, we show that guanabenz reproducibly lowers brain cyst burden up to 80% in chronically infected male and female BALB/cJ mice when given intraperitoneally but not when administered by gavage or in food. Regardless of the administration route, guanabenz reverses -induced hyperactivity in latently infected mice. In contrast, guanabenz increases cyst burden when given to chronically infected C57BL/6J mice yet still reverses -induced hyperactivity. Examination of the brains from chronically infected BALB/cJ and C57BL/6J mice shows that guanabenz decreases inflammation and perivascular cuffing in each strain. Our study establishes a robust model for cyst reduction in BALB/cJ mice and shows for the first time that it is possible to reverse a key behavioral change associated with latent toxoplasmosis. The rescue from parasite-induced hyperactivity correlates with a decrease in neuroinflammation rather than reduced cyst counts, suggesting that some behavioral changes arise from host responses to infection. is a common parasite of animals, including up to one-third of humans. The single-celled parasite persists within hosts for the duration of their life as tissue cysts, giving rise to chronic infection. Latent toxoplasmosis is correlated with neurological dysfunction in humans and results in dramatic behavioral changes in rodents. When infected, mice and rats adapt behaviors that make them more likely to be devoured by cats, the only host that supports the sexual stage of the parasite. In this study, we establish a new mouse model of tissue cyst depletion using a drug called guanabenz and show that it is possible to reverse a key behavior change back to normal in infected animals. We also show that the mechanism appears to have nothing to do with parasite cyst burden but rather the degree of neuroinflammation produced by chronic infection.
刚地弓形虫是一种感染了三分之一人类的细胞内寄生虫。这种感染是永久性的，因为复制形式（速殖子）转化为潜伏的组织囊肿形式（缓殖子），逃避宿主免疫，并且对当前的药物具有抗性。这些寄生囊肿的持续存在阻碍了治疗，并导致慢性感染，这与啮齿动物的行为变化和人类的神经疾病有关。这些行为变化是如何发生的，以及它们是由于寄生虫的操纵还是宿主对感染的反应，仍然是一个悬而未决的问题。我们之前曾表明胍那苄具有抗寄生虫活性；在这里，我们表明胍那苄可重复性地降低慢性感染的雄性和雌性 BALB/cJ 小鼠脑中囊肿负担高达 80%，当通过腹腔内给药而不是通过灌胃或在食物中给药时。无论给药途径如何，胍那苄均可逆转潜伏感染小鼠中的 - 引起的过度活动。相比之下，胍那苄增加慢性感染 C57BL/6J 小鼠的囊肿负担，但仍能逆转 - 引起的过度活动。对慢性感染的 BALB/cJ 和 C57BL/6J 小鼠的大脑进行检查表明，胍那苄可减少每种菌株的炎症和血管周围袖口。我们的研究建立了 BALB/cJ 小鼠中囊肿减少的强大模型，并首次表明有可能逆转与潜伏弓形虫病相关的关键行为变化。从寄生虫引起的过度活动中恢复与神经炎症的减少相关，而不是囊肿计数的减少，这表明一些行为变化是由宿主对感染的反应引起的。刚地弓形虫是一种常见的动物寄生虫，包括多达三分之一的人类。这种单细胞寄生虫在宿主的整个生命周期内作为组织囊肿存在，导致慢性感染。潜伏性弓形虫病与人类的神经功能障碍有关，并导致啮齿动物的行为发生巨大变化。当感染时，小鼠和大鼠适应行为，使它们更容易被唯一支持寄生虫有性阶段的宿主猫吞噬。在这项研究中，我们使用一种名为胍那苄的药物建立了一种新的组织囊肿耗竭小鼠模型，并表明有可能使感染动物的关键行为变化恢复正常。我们还表明，该机制似乎与寄生虫囊肿负担无关，而是与慢性感染引起的神经炎症程度有关。
