title: Altered drug susceptibility during host adaptation of a Plasmodium falciparum strain in a non-human primate model.
abstract: Infections with Plasmodium falciparum, the most pathogenic of the Plasmodium species affecting man, have been reduced in part due to artemisinin-based combination therapies. However, artemisinin resistant parasites have recently emerged in South-East Asia. Novel intervention strategies are therefore urgently needed to maintain the current momentum for control and elimination of this disease. In the present study we characterize the phenotypic and genetic properties of the multi drug resistant (MDR) P. falciparum Thai C2A parasite strain in the non-human Aotus primate model, and across multiple passages. Aotus infections with C2A failed to clear upon oral artesunate and mefloquine treatment alone or in combination, and ex vivo drug assays demonstrated reduction in drug susceptibility profiles in later Aotus passages. Further analysis revealed mutations in the pfcrt and pfdhfr loci and increased parasite multiplication rate (PMR) across passages, despite elevated pfmdr1 copy number. Altogether our experiments suggest alterations in parasite population structure and increased fitness during Aotus adaptation. We also present data of early treatment failures with an oral artemisinin combination therapy in a pre-artemisinin resistant P. falciparum Thai isolate in this animal model.
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard | T.H. Chan School of Public Health, Boston, MA, United States.|Center for the Evaluation of Antimalarial Drugs and Vaccines, Tropical Medicine Research/Instituto Conmemorativo Gorgas de Estudios de la Salud, Panamá City, Republic of Panama.
authors.forename: Nicanor
authors.initials: N
authors.lastname: Obaldía
authors.affiliation: Walter Reed Army Institute of Research, Silver Springs, MD, United States.
authors.forename: Geoffrey S
authors.initials: GS
authors.lastname: Dow
authors.affiliation: Walter Reed Army Institute of Research, Silver Springs, MD, United States.
authors.forename: Lucia
authors.initials: L
authors.lastname: Gerena
authors.affiliation: Department of Global Health, University of South Florida, Tampa, FL, United States.
authors.forename: Dennis
authors.initials: D
authors.lastname: Kyle
authors.affiliation: Center for the Evaluation of Antimalarial Drugs and Vaccines, Tropical Medicine Research/Instituto Conmemorativo Gorgas de Estudios de la Salud, Panamá City, Republic of Panama.
authors.forename: William
authors.initials: W
authors.lastname: Otero
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard | T.H. Chan School of Public Health, Boston, MA, United States.
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Mantel
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard | T.H. Chan School of Public Health, Boston, MA, United States.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Baro
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard | T.H. Chan School of Public Health, Boston, MA, United States.
authors.forename: Rachel
authors.initials: R
authors.lastname: Daniels
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard | T.H. Chan School of Public Health, Boston, MA, United States.
authors.forename: Angana
authors.initials: A
authors.lastname: Mukherjee
authors.affiliation: Center for Communicable Disease Dynamics and Harvard | T.H. Chan School of Public Health, Boston, MA, United States.|Department of Epidemiology, Harvard | T.H. Chan School of Public Health, Boston, MA, United States.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Childs
authors.affiliation: Center for Communicable Disease Dynamics and Harvard | T.H. Chan School of Public Health, Boston, MA, United States.|Department of Epidemiology, Harvard | T.H. Chan School of Public Health, Boston, MA, United States.
authors.forename: Caroline
authors.initials: C
authors.lastname: Buckee
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard | T.H. Chan School of Public Health, Boston, MA, United States.
authors.forename: Manoj T
authors.initials: MT
authors.lastname: Duraisingh
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard | T.H. Chan School of Public Health, Boston, MA, United States.|The Broad Institute of MIT and Harvard, Cambridge, MA, United States.|School of Nursing and Health Sciences, Simmons College, Boston, MA United States.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Volkman
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard | T.H. Chan School of Public Health, Boston, MA, United States.|The Broad Institute of MIT and Harvard, Cambridge, MA, United States.
authors.forename: Dyann F
authors.initials: DF
authors.lastname: Wirth
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard | T.H. Chan School of Public Health, Boston, MA, United States.
authors.forename: Matthias
authors.initials: M
authors.lastname: Marti
mesh_terms: D000220:Adaptation, Biological; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000494:pharmacology*; D016645:Aotidae; D037621:Artemisinins / Q000008:administration & dosage / Q000494:pharmacology; D000077332:Artesunate; D004195:Disease Models, Animal; D004351:Drug Resistance; D054884:Host-Pathogen Interactions; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology*; D021261:Parasitic Sensitivity Tests; D010641:Phenotype; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics; D011323:Primates; D040641:Quantitative Trait Loci; D017211:Treatment Failure
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D000077332:Artesunate