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Sci Rep. 2016 Feb 16;6:21216. doi: 10.1038/srep21216.

Altered drug susceptibility during host adaptation of a Plasmodium falciparum strain in a non-human primate model.

Author information

  • 1Department of Immunology and Infectious Diseases, Harvard | T.H. Chan School of Public Health, Boston, MA, United States.
  • 2Center for the Evaluation of Antimalarial Drugs and Vaccines, Tropical Medicine Research/Instituto Conmemorativo Gorgas de Estudios de la Salud, Panamá City, Republic of Panama.
  • 3Walter Reed Army Institute of Research, Silver Springs, MD, United States.
  • 4Department of Global Health, University of South Florida, Tampa, FL, United States.
  • 5Center for Communicable Disease Dynamics and Harvard | T.H. Chan School of Public Health, Boston, MA, United States.
  • 6Department of Epidemiology, Harvard | T.H. Chan School of Public Health, Boston, MA, United States.
  • 7The Broad Institute of MIT and Harvard, Cambridge, MA, United States.
  • 8School of Nursing and Health Sciences, Simmons College, Boston, MA United States.

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.

PMID:
26880111
PMCID:
PMC4754742
DOI:
10.1038/srep21216
[PubMed - indexed for MEDLINE]
Free PMC Article
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