Transmission of artemisinin-resistant malaria parasites to mosquitoes under antimalarial drug pressure
File(s)
Author(s)
Type
Journal Article
Abstract
Resistance to artemisinin-based combination therapy (ACT) in the Plasmodium falciparum parasite is threatening to reverse recent gains in reducing global deaths from malaria. Whilst resistance manifests as delayed parasite clearance in patients the phenotype can only spread geographically via the sexual stages and mosquito transmission. In addition to their asexual killing properties, artemisinin and its derivatives sterilise sexual male gametocytes. Whether resistant parasites overcome this sterilising effect has not, however, been fully tested. Here, we analysed P. falciparum clinical isolates from the Greater Mekong Subregion, each demonstrating delayed clinical clearance and known resistance-associated polymorphisms in Kelch13 (PfK13var). As well as demonstrating reduced asexual sensitivity to drug, certain PfK13var isolates demonstrated a marked reduction in sensitivity to artemisinin in an in vitro male gamete formation assay. Importantly, this same reduction in sensitivity was observed when the most resistant isolate was tested directly in mosquito feeds. These results indicate that, under artemisinin drug pressure, whilst sensitive parasites are blocked, resistant parasites continue transmission. This selective advantage for resistance transmission could favour acquisition of additional host-specificity or polymorphisms affecting partner drug sensitivity in mixed infections. Favoured resistance transmission under ACT coverage could have profound implications for the spread of multidrug resistant malaria beyond Southeast Asia.
Date Issued
2021-01
Date Acceptance
2020-10-20
Citation
Antimicrobial Agents and Chemotherapy, 2021, 65 (1), pp.1-17
ISSN
0066-4804
Publisher
American Society for Microbiology
Start Page
1
End Page
17
Journal / Book Title
Antimicrobial Agents and Chemotherapy
Volume
65
Issue
1
Copyright Statement
© 2020 Witmer et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/)
License URL
Sponsor
Wellcome Trust
Wellcome Trust
Medicines for Malaria Venture
Wellcome Trust
Medical Research Council (MRC)
The Royal Society
Medical Research Council (MRC)
Identifier
https://aac.asm.org/content/65/1/e00898-20/
Grant Number
100993/Z/13/Z
100993/Z/13/Z
MMV08/2800
109312/Z/15/Z
MR/N012275/1
DH140134
MR/R015600/1
Subjects
Science & Technology
Life Sciences & Biomedicine
Microbiology
Pharmacology & Pharmacy
Anopheles stephensi
Kelch13
Plasmodium falciparum
artemisinin combination therapies (ACTs)
gametocytes
multidrug-resistant malaria
transmission blocking
PLASMODIUM-FALCIPARUM MALARIA
MEFLOQUINE RESISTANCE
SOUTHEAST-ASIA
PFMDR1 GENE
OPEN-LABEL
DIHYDROARTEMISININ
HALOFANTRINE
COMBINATION
GAMETOCYTES
ARTESUNATE
Anopheles stephensi
Kelch13
Plasmodium falciparum
artemisinin combination therapies (ACTs)
gametocytes
multidrug-resistant malaria
transmission blocking
Microbiology
0605 Microbiology
1108 Medical Microbiology
1115 Pharmacology and Pharmaceutical Sciences
Publication Status
Published
Date Publish Online
2020-12-16