Department of Immunoparasitology, Osaka University, Osaka, Japan.
Department of Environmental Parasitology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
J Exp Med. 2019 Aug 5;216(8):1733-1748. doi: 10.1084/jem.20182227. Epub 2019 Jun 12.
The liver stage of the etiological agent of malaria, , is obligatory for successful infection of its various mammalian hosts. Differentiation of the rod-shaped sporozoites of 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 sporozoites in this organ. Here, we show that sporozoite differentiation into EEFs in the liver involves protein kinase C ζ-mediated NF-κB activation, which robustly induces the expression of C-X-C chemokine receptor type 4 (CXCR4) in hepatocytes and subsequently elevates intracellular Ca levels, thereby triggering sporozoite transformation into EEFs. Blocking CXCR4 expression by genetic or pharmacological intervention profoundly inhibited the liver-stage development of the rodent malaria parasite and the human parasite. Collectively, our experiments show that CXCR4 is a key host factor for development in the liver, and CXCR4 warrants further investigation for malaria prophylaxis.
疟原虫的肝脏阶段，是成功感染其各种哺乳动物宿主的必要条件。杆状的子孢子通过球状的外血红细胞前体（EEFs）的球型膨胀分化，对于寄生虫在肝脏中的发育是必不可少的。然而，对于调节这种器官中疟原虫子孢子形态转化的宿主因素知之甚少。在这里，我们表明，子孢子在肝脏中分化为 EEFs 涉及蛋白激酶 C ζ 介导的 NF-κB 激活，该激活强烈诱导肝实质细胞中 C-X-C 趋化因子受体 4（CXCR4）的表达，并随后升高细胞内 Ca 水平，从而触发子孢子转化为 EEFs。通过遗传或药理学干预阻断 CXCR4 的表达，可显著抑制啮齿动物疟原虫和人类疟原虫的肝脏阶段发育。总的来说，我们的实验表明，CXCR4 是肝脏中疟原虫发育的关键宿主因素，CXCR4 值得进一步研究以预防疟疾。
