Widespread Occurrence of the Plasmodium Falciparum Chloroquine Resistance Transporter (Pfcrt) Gene Haplotype SVMNT in P. Falciparum Malaria in India

Vathsala, P G; Pramanik, Atreyi; Sakthivel, Dhanasekaran; Devi, C. Usha; Pillai, C. R.; Subbarao, S. K.; Ghosh, SK; Tiwari, Shashikant; Sathyanarayan, T. S.; Deshpande, Prakash; Mishra, Gyan C.; Ranjit, Manoranjan; Dash, A. P.; Rangarajan, Pundi N.; Padmanaban, Govindarajan

doi:10.4269/ajtmh.2004.70.256

Cited by 82 publications

(81 citation statements)

References 12 publications

(19 reference statements)

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“…Similarly, findings have been reported from other sites, and it has been postulated that Pfmdr1 N86Y mutation may confer a compensatory advantage for coping 51N 51I 108S 108N 437A 437G 74M/75N/76K 74I/75E/76T 86N 86Y 184Y 184F Saudi Resident 89 46 88 47 135 0 0 123 89 39 3 123 Visitors 6 0 5 1 7 0 0 7 6 0 1 6 Total 95 46 93 48 143 0 0 130 95 39 4 129 Expatriates Resident 5 2 5 2 8 1 0 9 7 2 0 8 Visitors 18 10 18 10 28 0 2 23 16 10 1 22 Total 23 12 23 12 36 1 2 32 23 12 1 30 Total 118 58 116 60 178 1 2 162 118 53 5 with chloroquine pressure, which may vary in different parasite populations. 31,52 It has recently been suggested that some antimalarial drugs exert opposite directional selection on parasite genotypes. 16,53 For example, artemisinin-lumefantrine (AL) and amodiaquine (AQ) exert opposite within-host selective effects on the Pfmdr1 genes of P. falciparum.…”

Section: Discussionmentioning

confidence: 99%

Distribution of Drug Resistance Genotypes in Plasmodium falciparum in an Area of Limited Parasite Diversity in Saudi Arabia

Dajem

Al-Farsi

Al-Hashami

et al. 2012

The American Journal of Tropical Medicine and Hygiene

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Section: Discussionmentioning

confidence: 99%

Distribution of Drug Resistance Genotypes in Plasmodium falciparum in an Area of Limited Parasite Diversity in Saudi Arabia

Dajem

Al-Farsi

Al-Hashami

et al. 2012

The American Journal of Tropical Medicine and Hygiene

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“…In some parts of south-east Asia and most of South America, polymorphisms associated with resistance in one or both these genes are near-ubiquitous (Povoa et al, 1998;Zalis et al, 1998;Labbe et al, 2001;Vieira et al, 2001;Contreras et al, 2002;Cortese et al, 2002;Lopes et al, 2002;Vinayak et al, 2003;Casey et al, 2004;Huaman et al, 2004;Vathsala et al, 2004), a situation attributed to relatively higher levels of symptomatic infections and consequently increased levels of drug usage (Warhurst and Duraisingh, 2001;Hastings, 2003). In such circumstances, cessation of CQ use would not automatically lead to an expanded population of parasites carrying the wildtype alleles as the possibility of mixed infections, and thus competition between resistant and sensitive parasites, would be minimal.…”

Section: Discussionmentioning

confidence: 99%

pfmdr1 mutations associated with chloroquine resistance incur a fitness cost in Plasmodium falciparum

Hayward

Saliba

Kirk

2005

Molecular Microbiology

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SummaryEfforts to control malaria worldwide have been hindered by the development and expansion of parasite populations resistant to many first-line antimalarial compounds. Two of the best-characterized determinants of drug resistance in the human malaria parasite Plasmodium falciparum are pfmdr1 and pfcrt , although the mechanisms by which resistance is mediated by these genes is still not clear. In order to determine whether mutations in pfmdr1 associated with chloroquine resistance affect the capacity of the parasite to persist when drug pressure is removed, we conducted competition experiments between P. falciparum strains in which the endogenous pfmdr1 locus was modified by allelic exchange. In the absence of selective pressure, the component of chloroquine resistance attributable to mutations at codons 1034, 1042 and 1246 in the pfmdr1 gene also gave rise to a substantial fitness cost in the intraerythrocytic asexual stage of the parasite. The loss of fitness incurred by these mutations was calculated to be 25% with respect to an otherwise genetically identical strain in which wild-type polymorphisms had been substituted at these three codons. At least part of the fitness loss may be attributed to a diminished merozoite viability. These in vitro results support recent in vivo observations that in several countries where chloroquine use has been suspended because of widespread resistance, sensitive strains are re-emerging.

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“…One likely influence is the history of AQ and CQ use in these regions and the consequent selective pressure for pfcrt and pfmdr1 polymorphisms of one type or another. Haplotypes of pfcrt-encoding polymorphisms similar to those of the pfcrt alleles in South America and PNG have been reported from East Timor, Indonesia, the Philippines, Laos, India, and Iran (40)(41)(42)(43)(44)(45)(46)(47)(48)(49). In many of these regions AQ was widely used in the 1940s (50) and early 1950s before the advent of CQR (Fig.…”

Section: G8mentioning

confidence: 99%

Geographic patterns of Plasmodium falciparum drug resistance distinguished by differential responses to amodiaquine and chloroquine

Sá

Twu

Hayton

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

239

230

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Chloroquine (CQ) resistance (CQR) in Plasmodium falciparum originated from at least six foci in South America, Asia, and Oceania. Malaria parasites from these locations exhibit contrasting resistance phenotypes that are distinguished by point mutations and microsatellite polymorphisms in and near the CQR transporter gene, pfcrt, and the multidrug resistance transporter gene, pfmdr1. Amodiaquine (AQ), a 4-aminoquinoline related to CQ, is recommended and often used successfully against CQ-resistant P. falciparum in Africa, but it is largely ineffective across large regions of South America. The relationship of different pfcrt and pfmdr1 combinations to these drug-resistant phenotypes has been unclear. In two P. falciparum genetic crosses, particular pfcrt and pfmdr1 alleles from South America interact to yield greater levels of resistance to monodesethylamodiaquine (MDAQ; the active metabolite of AQ) than to CQ, whereas a pfcrt allele from Southeast Asia and Africa is linked to greater CQ than MDAQ resistance with all partner pfmdr1 alleles. These results, together with (i) available haplotype data from other parasites; (ii) evidence for an emerging focus of AQ resistance in Tanzania; and (iii) the persistence of 4-aminoquinoline-resistant parasites in South America, where CQ and AQ use is largely discontinued, suggest that different histories of drug use on the two continents have driven the selection of distinct suites of pfcrt and pfmdr1 mutations. Increasing use of AQ in Africa poses the threat of a selective sweep of highly AQ-resistant, CQ-resistant parasites with pfcrt and pfmdr1 mutations that are as advantaged and persistent as in South America.

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Widespread Occurrence of the Plasmodium Falciparum Chloroquine Resistance Transporter (Pfcrt) Gene Haplotype SVMNT in P. Falciparum Malaria in India

Cited by 82 publications

References 12 publications

Distribution of Drug Resistance Genotypes in Plasmodium falciparum in an Area of Limited Parasite Diversity in Saudi Arabia

Distribution of Drug Resistance Genotypes in Plasmodium falciparum in an Area of Limited Parasite Diversity in Saudi Arabia

pfmdr1 mutations associated with chloroquine resistance incur a fitness cost in Plasmodium falciparum

Geographic patterns of Plasmodium falciparum drug resistance distinguished by differential responses to amodiaquine and chloroquine

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