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Clinically relevant atovaquone-resistant human malaria parasites fail to transmit by mosquito
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Journal Article
Clinically relevant atovaquone-resistant human malaria parasites fail to transmit by mosquito
2023
Overview
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.
Malaria parasites from patients who fail atovaquone therapies are highly drug-resistant, with mutations at Y268 in cytochrome
b
. Here the authors show that this mutation results in multiple defects in the parasite’s development and prevents transmission from mosquitoes to mice.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/106
/ 13/31
/ 14/34
/ 14/63
/ 45
/ 45/22
/ 45/23
/ 45/29
/ 64/60
/ 82/1
/ Animals
/ Antimalarials - pharmacology
/ Antimalarials - therapeutic use
/ Antiparasitic Agents - therapeutic use
/ Atovaquone - therapeutic use
/ Defects
/ Humanities and Social Sciences
/ Humans
/ Malaria
/ Malaria, Falciparum - drug therapy
/ Mice
/ Mutation
/ Oocysts
/ Plasmodium falciparum - genetics
/ Science
/ Vaccines
