CXCR4 regulates Plasmodium development in mouse and human hepatocytes
CXCR4 regulates Plasmodium development in mouse and human hepatocytes
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DOI：
10.1084/jem.20182227
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发表时间：
2019-08-01
影响因子：
15.3
通讯作者：
Yamamoto, Masahiro
中科院分区：
文献类型：
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作者：
Bando, Hironori;Pradipta, Ariel;Yamamoto, Masahiro
疟疾病原体疟原虫的肝脏阶段是成功感染其各种哺乳动物宿主所必需的。疟原虫的杆状子孢子通过球根状扩张分化为球形红细胞外型（EEFs）是疟原虫在肝脏中发育所必需的。然而，很少有人知道宿主因子调节疟原虫子孢子在这个器官的形态转化。在这里，我们表明，子孢子分化成EEFs在肝脏中涉及蛋白激酶C zeta介导的NF-κ B激活，强烈诱导C-X-C趋化因子受体4型（CXCR 4）在肝细胞中的表达，随后升高细胞内Ca 2+水平，从而触发子孢子转化成EEFs。通过遗传或药物干预阻断CXCR 4表达，可显著抑制伯氏疟原虫啮齿类疟疾寄生虫和人类恶性疟原虫的肝脏阶段发育。总的来说，我们的实验表明，CXCR 4是疟原虫在肝脏中发育的关键宿主因子，CXCR 4值得进一步研究用于疟疾预防。
The liver stage of the etiological agent of malaria, Plasmodium, is obligatory for successful infection of its various mammalian hosts. Differentiation of the rod-shaped sporozoites of Plasmodium into spherical exoerythrocytic forms (EEFs) via bulbous expansion is essential for parasite development in the liver. However, little is known about the host factors regulating the morphological transformation of Plasmodium sporozoites in this organ. Here, we show that sporozoite differentiation into EEFs in the liver involves protein kinase C zeta-mediated NF-kappa B activation, which robustly induces the expression of C-X-C chemokine receptor type 4 (CXCR4) in hepatocytes and subsequently elevates intracellular Ca2+ levels, thereby triggering sporozoite transformation into EEFs. Blocking CXCR4 expression by genetic or pharmacological intervention profoundly inhibited the liver-stage development of the Plasmodium berghei rodent malaria parasite and the human Plasmodium falciparum parasite. Collectively, our experiments show that CXCR4 is a key host factor for Plasmodium development in the liver, and CXCR4 warrants further investigation for malaria prophylaxis.