Nanobody-mediated targeting of Plasmodium falciparum PfPIMMS43 can block malaria transmission in mosquitoes
Abstract The transition from ookinete to oocyst is a critical step in the Plasmodium falciparum lifecycle and an important target for malaria transmission-blocking strategies. PfPIMMS43, a surface protein of P. falciparum ookinetes and sporozoites, is critical for this transition and aids the parasi...
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Nature Portfolio
2025-04-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-08033-8 |
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| author | Chiamaka Valerie Ukegbu Mgeni Mohamed Astrid Hoermann Yuyan Qin Prisca A. Kweyamba Dickson Wilson Lwetoijera Nikolai Windbichler Sarah Moore George K. Christophides Dina Vlachou |
| author_facet | Chiamaka Valerie Ukegbu Mgeni Mohamed Astrid Hoermann Yuyan Qin Prisca A. Kweyamba Dickson Wilson Lwetoijera Nikolai Windbichler Sarah Moore George K. Christophides Dina Vlachou |
| author_sort | Chiamaka Valerie Ukegbu |
| collection | DOAJ |
| description | Abstract The transition from ookinete to oocyst is a critical step in the Plasmodium falciparum lifecycle and an important target for malaria transmission-blocking strategies. PfPIMMS43, a surface protein of P. falciparum ookinetes and sporozoites, is critical for this transition and aids the parasite in evading mosquito immune responses. Previous studies demonstrated that polyclonal PfPIMMS43 antibodies reduced P. falciparum infection in Anopheles mosquitoes. Here, building on these findings, we have developed high-affinity single-domain VHH antibodies (nanobodies) derived from llama heavy-chain-only antibodies. We have shown that these nanobodies bind both recombinant and endogenous PfPIMMS43 produced by P. falciparum ookinetes in the mosquito midgut. Importantly, they significantly reduce infection intensity and prevalence of laboratory and field strains of P. falciparum in An. coluzzii and An. gambiae, respectively. Epitope mapping has revealed that the nanobodies target conserved regions in the second half of PfPIMMS43, with homology modelling confirming epitope accessibility. These findings establish PfPIMMS43 as a promising transmission-blocking target. To enhance malaria control and elimination efforts, we propose an innovative strategy in which genetically modified mosquitoes express PfPIMMS43-specific nanobodies in their midguts and spread this trait in wild mosquito populations via gene drive technology. |
| format | Article |
| id | doaj-art-a0dc1748aa734364a8ff2d087616fade |
| institution | Kabale University |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-a0dc1748aa734364a8ff2d087616fade2025-08-20T03:52:24ZengNature PortfolioCommunications Biology2399-36422025-04-01811910.1038/s42003-025-08033-8Nanobody-mediated targeting of Plasmodium falciparum PfPIMMS43 can block malaria transmission in mosquitoesChiamaka Valerie Ukegbu0Mgeni Mohamed1Astrid Hoermann2Yuyan Qin3Prisca A. Kweyamba4Dickson Wilson Lwetoijera5Nikolai Windbichler6Sarah Moore7George K. Christophides8Dina Vlachou9Department of Life Sciences, Imperial College LondonEnvironmental Health and Ecological Sciences, Ifakara Health InstituteDepartment of Life Sciences, Imperial College LondonDepartment of Life Sciences, Imperial College LondonEnvironmental Health and Ecological Sciences, Ifakara Health InstituteEnvironmental Health and Ecological Sciences, Ifakara Health InstituteDepartment of Life Sciences, Imperial College LondonEnvironmental Health and Ecological Sciences, Ifakara Health InstituteDepartment of Life Sciences, Imperial College LondonDepartment of Life Sciences, Imperial College LondonAbstract The transition from ookinete to oocyst is a critical step in the Plasmodium falciparum lifecycle and an important target for malaria transmission-blocking strategies. PfPIMMS43, a surface protein of P. falciparum ookinetes and sporozoites, is critical for this transition and aids the parasite in evading mosquito immune responses. Previous studies demonstrated that polyclonal PfPIMMS43 antibodies reduced P. falciparum infection in Anopheles mosquitoes. Here, building on these findings, we have developed high-affinity single-domain VHH antibodies (nanobodies) derived from llama heavy-chain-only antibodies. We have shown that these nanobodies bind both recombinant and endogenous PfPIMMS43 produced by P. falciparum ookinetes in the mosquito midgut. Importantly, they significantly reduce infection intensity and prevalence of laboratory and field strains of P. falciparum in An. coluzzii and An. gambiae, respectively. Epitope mapping has revealed that the nanobodies target conserved regions in the second half of PfPIMMS43, with homology modelling confirming epitope accessibility. These findings establish PfPIMMS43 as a promising transmission-blocking target. To enhance malaria control and elimination efforts, we propose an innovative strategy in which genetically modified mosquitoes express PfPIMMS43-specific nanobodies in their midguts and spread this trait in wild mosquito populations via gene drive technology.https://doi.org/10.1038/s42003-025-08033-8 |
| spellingShingle | Chiamaka Valerie Ukegbu Mgeni Mohamed Astrid Hoermann Yuyan Qin Prisca A. Kweyamba Dickson Wilson Lwetoijera Nikolai Windbichler Sarah Moore George K. Christophides Dina Vlachou Nanobody-mediated targeting of Plasmodium falciparum PfPIMMS43 can block malaria transmission in mosquitoes Communications Biology |
| title | Nanobody-mediated targeting of Plasmodium falciparum PfPIMMS43 can block malaria transmission in mosquitoes |
| title_full | Nanobody-mediated targeting of Plasmodium falciparum PfPIMMS43 can block malaria transmission in mosquitoes |
| title_fullStr | Nanobody-mediated targeting of Plasmodium falciparum PfPIMMS43 can block malaria transmission in mosquitoes |
| title_full_unstemmed | Nanobody-mediated targeting of Plasmodium falciparum PfPIMMS43 can block malaria transmission in mosquitoes |
| title_short | Nanobody-mediated targeting of Plasmodium falciparum PfPIMMS43 can block malaria transmission in mosquitoes |
| title_sort | nanobody mediated targeting of plasmodium falciparum pfpimms43 can block malaria transmission in mosquitoes |
| url | https://doi.org/10.1038/s42003-025-08033-8 |
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