Interplay between liver and blood stages of Plasmodium infection dictates malaria severity via y8 T cells and IL-17-promoted stress erythropoiesis
Interplay between liver and blood stages of Plasmodium infection dictates malaria severity via y8 T cells and IL-17-promoted stress erythropoiesis
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DOI：
10.1016/j.immuni.2023.01.031
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发表时间：
2023-03-14
期刊：
影响因子：
32.4
通讯作者：
Mota, Maria M.
中科院分区：
文献类型：
--
作者：
Chora, Angelo Ferreira;Marques, Sofia;Mota, Maria M.
疟原虫在到达血流并感染红细胞之前在肝脏内复制。因为疟疾的临床表现只出现在感染的血液阶段，所以人们认为肝脏感染不会影响疾病的病理。通过建立肝脏和血液感染阶段分离的小鼠模型，我们表明，来自这两个阶段的信号集成决定了死亡结果。这种二分法依赖于肝脏阶段依赖的Vy4+Y8 T细胞的激活。随后的血液期寄生虫载量决定了它们的细胞因子谱，低寄生虫载量优先扩大产生IL-17的Y8 T细胞。IL-17促进髓外红细胞生成和伴随的网织红细胞增多，保护小鼠免受致死性实验性脑疟疾(ECM)的侵袭。过继转移红系前体细胞可使小鼠免于ECM。Y8 T细胞动力学模型表明，这种保护机制可能是在频繁暴露的个体中建立自然获得性疟疾免疫的关键。
Plasmodium replicates within the liver prior to reaching the bloodstream and infecting red blood cells. Because clinical manifestations of malaria only arise during the blood stage of infection, a perception exists that liver infection does not impact disease pathology. By developing a murine model where the liver and blood stages of infection are uncoupled, we showed that the integration of signals from both stages dictated mortality outcomes. This dichotomy relied on liver stage-dependent activation of Vy4+ y8 T cells. Subsequent blood stage parasite loads dictated their cytokine profiles, where low parasite loads preferentially expanded IL-17-producing y8 T cells. IL-17 drove extra-medullary erythropoiesis and concomitant reticulocytosis, which protected mice from lethal experimental cerebral malaria (ECM). Adoptive transfer of erythroid precur-sors could rescue mice from ECM. Modeling of y8 T cell dynamics suggests that this protective mechanism may be key for the establishment of naturally acquired malaria immunity among frequently exposed indi-viduals.