Within-host selection of drug resistance in a mouse model of repeated interrupted treatment of Plasmodium yoelii infection

• Published in: Malaria journal Vol. 16; no. 1; p. 216
• Main Authors: Nuralitha, Suci, Siregar, Josephine E, Syafruddin, Din, Hoepelman, Andy I M, Marzuki, Sangkot
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 23.05.2017; BioMed Central; BMC
• Subjects: Analysis; Animals; Antimalarials - therapeutic use; Atovaquone; Atovaquone - therapeutic use; Care and treatment; Cycles; Cytochrome; Cytochrome b; Cytochromes; Deoxyribonucleic acid; Diagnosis; Dihydrofolate reductase; DNA; Dose-Response Relationship, Drug; Drug development; Drug dosages; Drug resistance; Drug Resistance - genetics; Drug therapy; Drugs; Genotype & phenotype; Health aspects; Host selection; Human diseases; Infections; Malaria; Malaria - drug therapy; Malaria - parasitology; Mice; Mice, Inbred BALB C; Mitochondrial DNA; Mouse malaria model; Mutants; Mutation; Parasite resistance; Parasites; Pathogens; Phenotypes; Plasmodium falciparum; Plasmodium yoelii; Plasmodium yoelii - drug effects; Plasmodium yoelii - genetics; Prevention; Pyrimethamine; Pyrimethamine - therapeutic use; Repeated interrupted treatment; Selection, Genetic; Specific Pathogen-Free Organisms; Vector-borne diseases; Within-host selection of atovaquone resistance; St Louis Missouri; United States > US; Mouse malaria model; Within-host selection of atovaquone resistance; Repeated interrupted treatment; Plasmodium yoelii
• ISSN: 1475-2875; 1475-2875
• DOI: 10.1186/s12936-017-1860-6

To study within-host selection of resistant parasites, an important factor in the development of resistance to anti-malarial drugs, a mouse model of repeated interrupted malaria treatment (RIT) has been developed. The characteristics of within host selection of resistance to atovaquone and pyrimethamine in Plasmodium yoelii was examined in such a model. Treatment of P. yoelii infected mice, with atovaquone or pyrimethamine, was started at parasitaemia level of 3-5%, interrupted when reduced to less than 0.4%, and restarted following parasitaemia recovery to the initial level. Treatment cycles were repeated until stable phenotype resistance was observed. Plasmodium yoelii rapidly developed resistance to atovaquone (2.75 ± 1.06 cycles) and to pyrimethamine (5.4 ± 0.89 cycles) under RIT. A dose dependent phenomenon in the selection of atovaquone resistance mutations was observed. All mutations that underlie resistance to therapeutic doses of 0.3-1.44 mg kg BW were found to be in the Qo2 domain of the cytochrome b gene (I258M, F267I/L/S, L271V, K272R, L271V and K272R). Those associated with lower doses of 0.01-0.03 mg kg BW were in the Qo1 domain (M133I and T139S). The resistance mutations occurred at four of the 16 atovaquone putative drug binding sites suggested in P. falciparum. RIT of P. yoelii infected mice led to rapid development of resistance to atovaquone and pyrimethamine. The dose dependent selection of resistance mutants to atovaquone observed during RIT might reflect the outcome of two different causes of malaria treatment failure in human, repeated incomplete treatment with therapeutic dose and repeated inadequate treatment associated with sub-therapeutic dose, and need to be systematically investigated.