Plasmodium vivax latent liver infection is characterized by persistent hypnozoites, hypnozoite-derived schizonts, and time-dependent efficacy of primaquine.
Plasmodium vivax latent liver infection is characterized by persistent hypnozoites, hypnozoite-derived schizonts, and time-dependent efficacy of primaquine.
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DOI：
10.1016/j.omtm.2022.07.016
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发表时间：
2022-09-08
期刊：
影响因子：
--
通讯作者：
Sattabongkot, Jetsumon
中科院分区：
文献类型：
--
作者：
Flannery, Erika L.;Kangwanrangsan, Niwat;Chuenchob, Vorada;Roobsoong, Wanlapa;Fishbaugher, Matthew;Zhou, Kevin;Billman, Zachary P.;Martinson, Thomas;Olsen, Tayla M.;Schaefer, Carola;Campo, Brice;Murphy, Sean C.;Mikolajczak, Sebastian A.;Kappe, Stefan H. I.;Sattabongkot, Jetsumon
间日疟原虫是一种引起疟疾的病原体，它在肝脏中形成一种休眠形式（催眠虫），可在初次感染后数周、数月或数年激活，导致复发，其特征是继发性血期感染。这些无症状和无法检测到的潜伏性肝脏感染对全球根除疟疾的目标构成了重大障碍。我们使用人肝嵌合小鼠模型（FRG huHep）在体内模型系统中研究间日疟原虫的隐孢子虫潜伏期和激活。通过首先使用分裂体特异性抗疟疾工具化合物消除原发性肝脏分裂体，然后测量组织中继发性肝脏分裂体的复发和肝脏内寄生虫RNA的增加，可以证明催眠子的功能激活和继发性分裂体的形成。我们还发现，虽然伯氨喹不能立即消除肝脏中的催眠子，但它可以阻止正在发展的分裂体并阻止催眠子的激活，这与它在人类中的临床活性一致。我们的研究结果表明，FRG huHep模型可用于研究间日疟原虫感染和潜伏期的生物学，并评估抗复发药物的活性。采用肝嵌合人源化小鼠模型，观察间日疟原虫标准护理药物对体内催眠子的影响。没有观察到寄生虫的立即清除，但增加的孵育时间加上工具化合物去除滞留的药物治疗寄生虫，可以对根治药物进行试验。
Plasmodium vivax is a malaria-causing pathogen that establishes a dormant form in the liver (the hypnozoite), which can activate weeks, months, or years after the primary infection to cause a relapse, characterized by secondary blood-stage infection. These asymptomatic and undetectable latent liver infections present a significant obstacle to the goal of global malaria eradication. We use a human liver-chimeric mouse model (FRG huHep) to study P. vivax hypnozoite latency and activation in an in vivo model system. Functional activation of hypnozoites and formation of secondary schizonts is demonstrated by first eliminating primary liver schizonts using a schizont-specific antimalarial tool compound, and then measuring recurrence of secondary liver schizonts in the tissue and an increase in parasite RNA within the liver. We also reveal that, while primaquine does not immediately eliminate hypnozoites from the liver, it arrests developing schizonts and prevents activation of hypnozoites, consistent with its clinical activity in humans. Our findings demonstrate that the FRG huHep model can be used to study the biology of P. vivax infection and latency and assess the activity of anti-relapse drugs. The liver-chimeric humanized mouse model is used to show the effect of P. vivax standard of care drugs on hypnozoites in vivo. Immediate clearance of parasites is not observed, yet increased incubation time together with removal of arrested drug-treated parasites with tool compounds allows the testing of radical cure drugs.
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影响因子：
30.3
作者：
Gural N;Mancio-Silva L;Miller AB;Galstian A;Butty VL;Levine SS;Patrapuvich R;Desai SP;Mikolajczak SA;Kappe SHI;Fleming HE;March S;Sattabongkot J;Bhatia SN
通讯作者：
Bhatia SN
影响因子：
46.9
作者：
Azuma, Hisaya;Paulk, Nicole;Grompe, Markus
通讯作者：
Grompe, Markus
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
158.5
作者：
Llanos-Cuentas, A.;Lacerda, M. V. G.;Green, J. A.
通讯作者：
Green, J. A.
影响因子：
82.9
作者：
Dembele, Laurent;Franetich, Jean-Francois;Mazier, Dominique
通讯作者：
Mazier, Dominique