Host complement C3 promotes malaria transmission by killing symbiotic bacteria in the mosquito midgut

• 成果类型: Article
• 署名作者: 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
• 署名单位: Army Medical University; Xiamen University; Chinese Academy of Sciences; Shanghai Institute of Immunity and Infection, CAS; Pasteur Network; University of Chinese Academy of Sciences, CAS; Chinese Academy of Sciences; Center for Excellence in Molecular Plant Sciences, CAS
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11016
• DOI: 10.1073/pnas.2424570122
• 发表日期: 2025-06-03
• 关键词: plasmodium-falciparum; activation; nitration; infection; invasion; immunity; cells

摘要

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 Plasmodium infection, significantly enhanced rodent malaria infection in laboratory-reared mosquitoes. This effect was recapitulated in field-caught Anopheles sinensis 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 Elizabethkingia anophelis (E. anophelis)-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 Plasmodium falciparum (P. falciparum) infection, while increased the efficacy of anti-Pfs25 antibodies to blocking P. falciparum 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.