He Biao, Li Meilin, Guo Shuai, Zhu Feng, Jiao Zhiwei, Li Jianyong, Tan Nie, Jiao Shiming, Liu Taiping, Zhang Jian, Fan Yongling, Gao Yuanli, Zhou Taoli, Li Jian, Huang Wei, Jiang Lubin, Lin Zurui, Wang Sibao, Xu Wenyue
Department of Pathogenic Biology, Army Medical University, Chongqing 400038, China.
State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
Proc Natl Acad Sci U S A. 2025 Jun 3;122(22):e2424570122. doi: 10.1073/pnas.2424570122. Epub 2025 May 28.
Host-derived factors ingested during mosquito blood feeding are poorly understood modulators of malaria transmission. Here, we demonstrated that host complement C3, acquired by mosquitoes during infection, significantly enhanced rodent malaria infection in laboratory-reared mosquitoes. This effect was recapitulated in field-caught mosquitoes, confirming its relevance to malaria transmission in a more natural setting. Moreover, host-derived C3 significantly reduced the efficacy of anti-Pfs25 antibodies in blocking malaria transmission. Mechanistically, host-derived C3 lyses the mosquito midgut symbiont ()-a bacterium that intrinsically suppresses parasite development by blocking the zygote-to-ookinete transition. Strikingly, host-derived C3 in mosquitoes appears to be activated by the alternative pathway, and inhibiting Factor B with Iptacopan (LNP023) reduced () infection, while increased the efficacy of anti-Pfs25 antibodies to blocking transmission in the standard membrane-feeding assay. Therefore, this study describes a strategy of the malaria parasite to utilize host complement C3 to promote its transmission and provides us with an avenue to block malaria transmission and improve the blocking efficacy of anti-Pfs25 antibodies by the inhibition of C3 activation.
在蚊子吸食血液过程中摄入的宿主来源因子是对疟疾传播了解甚少的调节因子。在此，我们证明了蚊子在感染期间获得的宿主补体C3，在实验室饲养的蚊子中显著增强了啮齿动物疟疾感染。在野外捕获的蚊子中也重现了这种效应，证实了其在更自然环境中与疟疾传播的相关性。此外，宿主来源的C3显著降低了抗Pfs25抗体阻断疟疾传播的效力。从机制上讲，宿主来源的C3裂解蚊子中肠共生菌（）——一种通过阻断合子向动合子转变来内在抑制寄生虫发育的细菌。引人注目的是，蚊子中宿主来源的C3似乎通过替代途径被激活，用Iptacopan（LNP023）抑制因子B可减少（）感染，同时在标准膜饲实验中提高抗Pfs25抗体阻断传播的效力。因此，本研究描述了疟原虫利用宿主补体C3促进其传播的策略，并为我们提供了一条通过抑制C3激活来阻断疟疾传播和提高抗Pfs25抗体阻断效力的途径。
