Plasmodium yoelii Erythrocyte-Binding-like Protein Modulates Host Cell Membrane Structure, Immunity, and Disease Severity
Plasmodium yoelii Erythrocyte-Binding-like Protein Modulates Host Cell Membrane Structure, Immunity, and Disease Severity
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DOI：
10.1128/mbio.02995-19
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发表时间：
2020-01-01
期刊：
影响因子：
6.4
通讯作者：
Su, Xin-zhuan
中科院分区：
文献类型：
--
作者：
Peng, Yu-chih;Qi, Yanwei;Su, Xin-zhuan
红细胞结合样蛋白(EBL)在疟疾原虫入侵红细胞(RBC)中起重要作用，但EBL蛋白在调节宿主免疫反应中的作用尚不清楚。在这里，我们证明了约氏疟原虫EBL(PyEBL)可以通过调节受感染红细胞(IRBCs)的表面结构和宿主免疫反应来决定疾病的严重性。我们在C57BL/6小鼠中发现了约氏疟原虫N67株和N67C寄生虫之间的一个氨基酸替换(741[C741Y]位由C变为Y)。C741Y等位基因的交换相应地改变了寄生虫的生长和宿主存活。C741Y还改变了iRBC在裂殖子和细胞质中的蛋白质加工和运输，减少了PyEBL与带3的结合，增加了磷脂酰丝氨酸(PS)的表面暴露，并增加了iRBC的渗透脆性，但不影响RBC的体外侵袭。修饰后的IRBC表面可触发PS-CD36介导的iRBC吞噬、宿主I型干扰素信号传导和T细胞分化，从而提高宿主存活率。这项研究揭示了PyEBL在调节宿主-病原体相互作用和先天性免疫反应中以前未知的作用，这可能被探索用于制定疾病控制策略。输入性疟疾是一种致命的寄生虫病，每年继续困扰数亿人。感染疟疾寄生虫可能是无症状的，症状轻微，也可能是致命的，这取决于宿主免疫反应的微妙平衡。疟原虫通过与宿主受体相互作用进入宿主红细胞(RBC)，如红细胞结合样蛋白(EBL)和宿主Duffy抗原趋化因子受体(DARC)。约氏疟原虫EBL(PyEBL)在寄生虫侵袭红细胞过程中起重要作用。在这里，我们表明，PyEBL还通过调节宿主免疫反应，特别是I型干扰素(IFN-I)信号来影响疾病严重程度。这一发现为PyEBL赋予了新的功能，并为制定疾病控制策略提供了一种机制。
Erythrocyte-binding-like (EBL) proteins are known to play an important role in malaria parasite invasion of red blood cells (RBCs); however, any roles of EBL proteins in regulating host immune responses remain unknown. Here, we show that Plasmodium yoelii EBL (PyEBL) can shape disease severity by modulating the surface structure of infected RBCs (iRBCs) and host immune responses. We identified an amino acid substitution (a change of C to Y at position 741 [C741Y]) in the protein trafficking domain of PyEBL between isogenic P. yoellii nigeriensis strain N67 and N67C parasites that produce different disease phenotypes in C57BL/6 mice. Exchanges of the C741Y alleles altered parasite growth and host survival accordingly. The C741Y substitution also changed protein processing and trafficking in merozoites and in the cytoplasm of iRBCs, reduced PyEBL binding to band 3, increased phosphatidylserine (PS) surface exposure, and elevated the osmotic fragility of iRBCs, but it did not affect invasion of RBCs in vitro. The modified iRBC surface triggered PS-CD36-mediated phagocytosis of iRBCs, host type I interferon (IFN-I) signaling, and T cell differentiation, leading to improved host survival. This study reveals a previously unknown role of PyEBL in regulating host-pathogen interaction and innate immune responses, which may be explored for developing disease control strategies.IMPORTANCE Malaria is a deadly parasitic disease that continues to afflict hundreds of millions of people every year. Infections with malaria parasites can be asymptomatic, with mild symptoms, or fatal, depending on a delicate balance of host immune responses. Malaria parasites enter host red blood cells (RBCs) through interactions between parasite ligands and host receptors, such as erythrocyte-binding-like (EBL) proteins and host Duffy antigen receptor for chemokines (DARC). Plasmodium yoelii EBL (PyEBL) is known to play a role in parasite invasion of RBCs. Here, we show that PyEBL also affects disease severity through modulation of host immune responses, particularly type I interferon (IFN-I) signaling. This discovery assigns a new function to PyEBL and provides a mechanism for developing disease control strategies.