Dual effector population modification gene-drive strains of the African malaria mosquitoes, Anopheles gambiae and Anopheles coluzzii .

Autor:	Carballar-Lejarazú R; Department of Microbiology & Molecular Genetics, University of California, Irvine, CA 92697-4025., Dong Y; W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Malaria Research Institute, Johns Hopkins University, Baltimore, MD 21205., Pham TB; Department of Microbiology & Molecular Genetics, University of California, Irvine, CA 92697-4025., Tushar T; Department of Microbiology & Molecular Genetics, University of California, Irvine, CA 92697-4025., Corder RM; Divisions of Epidemiology and Biostatistics, School of Public Health, University of California, Berkeley, CA 94720., Mondal A; Divisions of Epidemiology and Biostatistics, School of Public Health, University of California, Berkeley, CA 94720., Sánchez C HM; Divisions of Epidemiology and Biostatistics, School of Public Health, University of California, Berkeley, CA 94720., Lee HF; Department of Microbiology & Molecular Genetics, University of California, Irvine, CA 92697-4025., Marshall JM; Divisions of Epidemiology and Biostatistics, School of Public Health, University of California, Berkeley, CA 94720., Dimopoulos G; W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Malaria Research Institute, Johns Hopkins University, Baltimore, MD 21205., James AA; Department of Microbiology & Molecular Genetics, University of California, Irvine, CA 92697-4025.; Department of Molecular Biology & Biochemistry, University of California, Irvine, CA 92697-3900.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2023 Jul 18; Vol. 120 (29), pp. e2221118120. Date of Electronic Publication: 2023 Jul 10.
DOI:	10.1073/pnas.2221118120
Abstrakt:	Proposed genetic approaches for reducing human malaria include population modification, which introduces genes into vector mosquitoes to reduce or prevent parasite transmission. We demonstrate the potential of Cas9/guide RNA (gRNA)-based gene-drive systems linked to dual antiparasite effector genes to spread rapidly through mosquito populations. Two strains have an autonomous gene-drive system coupled to dual anti- Plasmodium falciparum effector genes comprising single-chain variable fragment monoclonal antibodies targeting parasite ookinetes and sporozoites in the African malaria mosquitoes Anopheles gambiae (AgTP13) and Anopheles coluzzii (AcTP13). The gene-drive systems achieved full introduction within 3 to 6 mo after release in small cage trials. Life-table analyses revealed no fitness loads affecting AcTP13 gene-drive dynamics but AgTP13 males were less competitive than wild types. The effector molecules reduced significantly both parasite prevalence and infection intensities. These data supported transmission modeling of conceptual field releases in an island setting that shows meaningful epidemiological impacts at different sporozoite threshold levels (2.5 to 10 k) for human infection by reducing malaria incidence in optimal simulations by 50 to 90% within as few as 1 to 2 mo after a series of releases, and by ≥90% within 3 mo. Modeling outcomes for low sporozoite thresholds are sensitive to gene-drive system fitness loads, gametocytemia infection intensities during parasite challenges, and the formation of potentially drive-resistant genome target sites, extending the predicted times to achieve reduced incidence. TP13-based strains could be effective for malaria control strategies following validation of sporozoite transmission threshold numbers and testing field-derived parasite strains. These or similar strains are viable candidates for future field trials in a malaria-endemic region.
Databáze:	MEDLINE
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