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Effects of Plasmodium falciparum Mixed Infections on In Vitro Antimalarial Drug Tests and Genotyping

Studying drug resistance in Plasmodium falciparum requires accurate measurement of parasite response to a drug. Factors such as mixed infection of drug-resistant and -sensitive parasites can influence drug test outcome. Polymorphic DNA sequences are frequently used to detect mixed infections; infections with a single genotype or having a minor allele smaller than a subjectively selected cut-off value are often considered single infection. We studied the effects of mixed parasite populations containing various ratios of parasites resistant and sensitive to chloroquine on outcomes of drug tests and how ratios of parasite mixtures correlated with genotypes using polymerase chain reaction–based methods. Our results show that a mixture with a resistant population as low as 10% could greatly impact a drug test outcome. None of the genotyping methods could reliably detect minor DNA alleles at 10%. Mixed infection presents a serious problem for drug tests, and genotyping using microsatellite or other methods may not reliably reflect true ratios of alleles.

Received February 18, 2008. Accepted for publication May 8, 2008.

Acknowledgments: The authors thank Dr. Roland Cooper for help in developing drug assays, Dr. Lubing Jiang for help in qPCR, Dr. Tim Anderson for critical comments, and intramural editor Brenda Rae Marshall for assistance.

Financial support: This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; and the National Basic Research Program of China, 973 Program 2007CB513103.

^* Address correspondence to Xin-zhuan Su, Laboratory of Malaria and Vector Research, National Institutes of Health, 12735 Twinbrook Parkway, Room 3E24B, Rockville, MD 20852. E-mail: xsu{at}niaid.nih.gov

Authors’ addresses: Shengfa Liu, Jianbing Mu, Hongying Jiang, and Xin-zhuan Su, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 9000 Rockville Pike, MD 20892-8132, Tel: 1-301-402-0876, Fax: 1-301-402-2201, E-mails: liuxie{at}xmu.edu.cn, jmu{at}niaid.nih.gov, hojiang{at}niaid.nih.gov, and xsu{at}niaid.nih.gov. Shengfa Liu is also at the Key Laboratory of the Ministry of Education for Cell Biology and Tumour Cell Engineering, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, The People’s Republic of China.

Reprint requests: Xin-zhuan Su, Laboratory of Malaria and Vector Research, National Institutes of Health, 12735 Twinbrook Parkway, Room 3E24B, Rockville, MD 20852, E-mail: xsu{at}niaid.nih.gov.