ARTICLE: Clinically relevant atovaquone-resistant human malaria parasites fail to transmit by mosquito
AUTHORS: Victoria A Balta, Deborah Stiffler, Abeer Sayeed, Abhai K Tripathi, Rubayet Elahi, Godfree Mlambo, Rahul P Bakshi, Amanda G Dziedzic, Anne E Jedlicka, Elizabeth Nenortas, Keyla Romero-Rodriguez, Matthew A Canonizado, Alexis Mann, Andrew Owen, David J Sullivan, Sean T Prigge, Photini Sinnis, Theresa A Shapiro
JOURNAL: Nat Commun. 2023 Oct 12;14(1):6415. doi: 10.1038/s41467-023-42030-x
Abstract
Long-acting injectable medications, such as atovaquone, offer the prospect of a "chemical vaccine" for malaria, combining drug efficacy with vaccine durability. However, selection and transmission of drug-resistant parasites is of concern. Laboratory studies have indicated that atovaquone resistance disadvantages parasites in mosquitoes, but lack of data on clinically relevant Plasmodium falciparum has hampered integration of these variable findings into drug development decisions. Here we generate atovaquone-resistant parasites that differ from wild type parent by only a Y268S mutation in cytochrome b, a modification associated with atovaquone treatment failure in humans. Relative to wild type, Y268S parasites evidence multiple defects, most marked in their development in mosquitoes, whether from Southeast Asia (Anopheles stephensi) or Africa (An. gambiae). Growth of asexual Y268S P. falciparum in human red cells is impaired, but parasite loss in the mosquito is progressive, from reduced gametocyte exflagellation, to smaller number and size of oocysts, and finally to absence of sporozoites. The Y268S mutant fails to transmit from mosquitoes to mice engrafted with human liver cells and erythrocytes. The severe-to-lethal fitness cost of clinically relevant atovaquone resistance to P. falciparum in the mosquito substantially lessens the likelihood of its transmission in the field.
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