2. Academic Validation
  3. Host complement C3 promotes malaria transmission by killing symbiotic bacteria in the mosquito midgut

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

  • Proc Natl Acad Sci U S A. 2025 Jun 3;122(22):e2424570122. doi: 10.1073/pnas.2424570122.
Biao He 1,  Meilin Li 1,  Shuai Guo 1,  Feng Zhu 1,  Zhiwei Jiao 2,  Jianyong Li 1,  Nie Tan 1,  Shiming Jiao 1,  Taiping Liu 1,  Jian Zhang 1,  Yongling Fan 1,  Yuanli Gao 1,  Taoli Zhou 1,  Jian Li 2,  Wei Huang 3,  Lubin Jiang 3,  Zurui Lin 4,  Sibao Wang 5,  Wenyue Xu 1 6
Affiliations

Affiliations

  • 1 Department of Pathogenic Biology, Army Medical University, Chongqing 400038, China.
  • 2 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
  • 3 Key Laboratory of Molecular Virology and Immunology, Shanghai institute of immunity and infection, Institut Pasteur of Shanghai, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200030, China.
  • 4 Dvision of Malaria Control, Yunnan Institute of Parasitic Diseases, Pu'er, Yunnan 655000, China.
  • 5 New Cornerstone Science Laboratory, Chinese Academy of Sciences Key Laboratory of Insect Developmental and Evolutionary Biology, Chinese Academy of Sciences Center for Excellence in Molecular Plant Sciences, Shanghai Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai 200030, China.
  • 6 Key Laboratory of Extreme Environmental Medicine, Ministry of Education of China, Chongqing, 400038, China.
PMID: 40434644 DOI: 10.1073/pnas.2424570122
Abstract

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.

Keywords

complement C3; malaria parasite; microbiota; mosquitoes; transmission.

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