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<p><i>Plasmodium falciparum</i> employs sophisticated strategies to subvert host immunity, whereas the specific parasite-derived factors governing this critical process remain elusive. Here, by utilizing <i>P. falciparum</i> 3D7 and <i>P. berghei</i> ANKA infection models, we investigated the role of parasite-derived PI3K in immune evasion, and found that <i>Plasmodium</i> PI3K prevents the externalization of phosphatidylserine (PS), a canonical prophagocytic ‘eat-me’ signal. Inhibiting PI3K activity in infected red blood cells (iRBCs) significantly increased M2 macrophage polarization and iRBC recognition. Mechanistically, we identified that <i>Pf</i>PI3K preserves mitochondrial membrane potential and prevents calcium efflux by promoting the 2-hydroxyisobutyrylation of the 14–3-3 protein to maintain a calcium-homeostatic environment. Therefore, <i>Pf</i>PI3K could phosphorylate <i>P. falciparum</i> phospholipid scramblase 1 (<i>Pf</i>PLSCR1) to maintain PS internalization in iRBCs while preventing their exposure to immune cells. Collectively, these results revealed a mechanism through which <i>Plasmodium</i> parasites leverage PI3K to actively suppress PS-associated ‘eat-me’ signalling in iRBCs, thereby circumventing host macrophage-mediated surveillance and facilitating persistent infection.</p>

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Plasmodium PI3K suppresses the externalization of phosphatidylserine on infected erythrocytes

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月14日

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  • Kexin Zheng,
  • Qilong Li,
  • Ning Jiang,
  • Ang Li,
  • Yanxin Zhang,
  • Ye Zhang,
  • Zhiming Wei,
  • Anni Feng,
  • Tong Liu,
  • Xin Li,
  • Yiwei Zhang,
  • Xiaoyu Sang,
  • Ying Feng,
  • Ran Chen,
  • Qijun Chen

摘要

Plasmodium falciparum employs sophisticated strategies to subvert host immunity, whereas the specific parasite-derived factors governing this critical process remain elusive. Here, by utilizing P. falciparum 3D7 and P. berghei ANKA infection models, we investigated the role of parasite-derived PI3K in immune evasion, and found that Plasmodium PI3K prevents the externalization of phosphatidylserine (PS), a canonical prophagocytic ‘eat-me’ signal. Inhibiting PI3K activity in infected red blood cells (iRBCs) significantly increased M2 macrophage polarization and iRBC recognition. Mechanistically, we identified that PfPI3K preserves mitochondrial membrane potential and prevents calcium efflux by promoting the 2-hydroxyisobutyrylation of the 14–3-3 protein to maintain a calcium-homeostatic environment. Therefore, PfPI3K could phosphorylate P. falciparum phospholipid scramblase 1 (PfPLSCR1) to maintain PS internalization in iRBCs while preventing their exposure to immune cells. Collectively, these results revealed a mechanism through which Plasmodium parasites leverage PI3K to actively suppress PS-associated ‘eat-me’ signalling in iRBCs, thereby circumventing host macrophage-mediated surveillance and facilitating persistent infection.