TY - JOUR
T1 - Transmission of artemisinin-resistant malaria parasites to mosquitoes under antimalarial drug pressure
AU - Witmer, Kathrin
AU - Dahalan, Farah A.
AU - Delves, Michael J.
AU - Yahiya, Sabrina
AU - Watson, Oliver J.
AU - Straschil, Ursula
AU - Chiwcharoen, Darunee
AU - Sornboon, Boodtee
AU - Pukrittayakamee, Sasithon
AU - Pearson, Richard D.
AU - Howick, Virginia M.
AU - Lawniczak, Mara K. N.
AU - White, Nicholas J.
AU - Dondorp, Arjen M.
AU - Okell, Lucy C.
AU - Chotivanich, Kesinee
AU - Ruecker, Andrea
AU - Baum, Jake
N1 - Funding Information: This work was supported by a joint Medical Research Council (MRC) UK Newton and National Science and Technology Development Agency (NSTDA), Thailand award (MR/ N012275/1 to J.B., S.P., N.J.W., and K.C.). Further support came from the Medicines for Malaria Venture (MMV) (MMV08/2800 to J.B.). J.B. is supported by an Investigator Award from Wellcome (100993/Z/13/Z). N.J.W. is supported by Wellcome with a Principal Research Fellowship (107886/Z/15/Z). The Mahidol University Oxford Tropical Medicine Research Program is funded by Wellcome (AMD 106698/Z/14/A). The Wellcome Sanger Institute is funded by Wellcome (206194/Z/17/Z), which supports M.K.N.L. O.J.W. would like to acknowledge funding from a Wellcome Trust PhD Studentship (109312/Z/15/Z). S.Y. would like to acknowledge PhD funding from an EPSRC Doctoral Training Partnership Award to Imperial College London. We declare no conflicts of interest. Funding Information: This work was supported by a joint Medical Research Council (MRC) UK Newton and National Science and Technology Development Agency (NSTDA), Thailand award (MR/ N012275/1 to J.B., S.P., N.J.W., and K.C.). Further support came from the Medicines for Malaria Venture (MMV) (MMV08/2800 to J.B.). J.B. is supported by an Investigator Award from Wellcome (100993/Z/13/Z). N.J.W. is supported by Wellcome with a Principal Research Fellowship (107886/Z/15/Z). The Mahidol University Oxford Tropical Medicine Research Program is funded by Wellcome (AMD 106698/Z/14/A). The Wellcome Sanger Institute is funded by Wellcome (206194/Z/17/Z), which supports M.K.N.L. O.J.W. would like to acknowledge funding from a Wellcome Trust PhD Studentship (109312/Z/15/Z). S.Y. would like to acknowledge PhD funding from an EPSRC Doctoral Training Partnership Award to Imperial College London. We declare no conflicts of interest. We thank the gametocyte team at Imperial College London for ongoing provision of gametocytes, in particular Alisje Churchyard, Irene Garc?a Barbaz?n, Joshua Blight, and Eliana Real and staff of the sequencing facility at the Wellcome Sanger Institute for their contribution. We also thank Mark Tunnicliff for ongoing provision of A. stephensi mosquitoes, Olivo Miotto (MORU) for sharing genome sequences of the parasite isolates and for helping in the analysis of SNP calling, and Chanaki Amaratunga (MORU) for constructive discussions. Figures 3a and b were created with BioRender.com. M.J.D., A.R., K.C., and J.B. conceptualized the study; K.W., F.A.D., M.J.D., and A.R. designed experiments; experiments were undertaken by K.W., F.A.D., M.J.D., S.Y., U.S., D.C., A.R., and B.S.; R.D.P., V.M.H., M.K.N.L., K.W., and A.R. generated and curated the genome data; modeling components were designed and executed by O.J.W. and L.C.O. S.P., N.J.W., A.M.D., and K.C. supervised collection of clinical isolates used in the study. K.W., F.A.D., A.R., M.J.D., and J.B. wrote the manuscript. All authors contributed to overall editing and manuscript approval. Publisher Copyright: © 2020 Witmer et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/1/1
Y1 - 2021/1/1
N2 - Resistance to artemisinin-based combination therapy (ACT) in the Plasmodium falciparum parasite is threatening to reverse recent gains in reducing global deaths from malaria. While 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 sterilize sexual male gametocytes. Whether resistant parasites overcome this sterilizing effect has not, however, been fully tested. Here, we analyzed P. falciparum clinical isolates from the Greater Mekong Subregion, each demonstrating delayed clinical clearance and known resistance-associated polymorphisms in the Kelch13 (PfK13var) gene. 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, while sensitive parasites are blocked, resistant parasites continue transmission. This selective advantage for resistance transmission could favor acquisition of additional host-specificity or polymorphisms affecting partner drug sensitivity in mixed infections. Favored resistance transmission under ACT coverage could have profound implications for the spread of multidrug-resistant malaria beyond Southeast Asia.
AB - Resistance to artemisinin-based combination therapy (ACT) in the Plasmodium falciparum parasite is threatening to reverse recent gains in reducing global deaths from malaria. While 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 sterilize sexual male gametocytes. Whether resistant parasites overcome this sterilizing effect has not, however, been fully tested. Here, we analyzed P. falciparum clinical isolates from the Greater Mekong Subregion, each demonstrating delayed clinical clearance and known resistance-associated polymorphisms in the Kelch13 (PfK13var) gene. 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, while sensitive parasites are blocked, resistant parasites continue transmission. This selective advantage for resistance transmission could favor acquisition of additional host-specificity or polymorphisms affecting partner drug sensitivity in mixed infections. Favored resistance transmission under ACT coverage could have profound implications for the spread of multidrug-resistant malaria beyond Southeast Asia.
KW - Anopheles stephensi
KW - Artemisinin combination therapies (ACTs)
KW - Gametocytes
KW - Kelch13
KW - Multidrug-resistant malaria
KW - Plasmodium falciparum
KW - Transmission blocking
UR - http://www.scopus.com/inward/record.url?scp=85098642672&partnerID=8YFLogxK
U2 - https://doi.org/10.1128/AAC.00898-20
DO - https://doi.org/10.1128/AAC.00898-20
M3 - Article
C2 - 33139275
SN - 0066-4804
VL - 65
JO - Antimicrobial agents and chemotherapy
JF - Antimicrobial agents and chemotherapy
IS - 1
M1 - e00898-20
ER -