Evidence for Regulation of Hemoglobin Metabolism and Intracellular Ionic Flux by the Plasmodium falciparum Chloroquine Resistance Transporter

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Lee, Andrew H. ^[1] ; Dhingra, Satish K. ^[1] ; Lewis, Ian A. ^{[2, 3]} ; Singh, Maneesh K. ^{[4, 5]} ; Siriwardana, Amila ^{[6, 7]} ; Dalal, Seema ^[8] ; Rubiano, Kelly ^[1] ; Klein, Matthias S. ^[2] ; Baska, Katelynn S. ^[3] ; Krishna, Sanjeev ^[9] ; Klemba, Michael ^[8] ; Roepe, Paul D. ^{[6, 7]} ; Llinas, Manuel ^{[10, 11, 12]} ; Garcia, Celia R. S. ^{[4, 13]} ; Fidock, David A. ^{[1, 14]}

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^[1] Columbia Univ, Med Ctr, Dept Microbiol & Immunol, New York, NY 10027 - USA

^[2] Univ Calgary, Dept Biol Sci, Calgary, AB - Canada

^[3] Princeton Univ, Lewis Sigler Inst Integrat Genom, Princeton, NJ 08544 - USA

^[4] Univ Sao Paulo, Inst Biomed Sci, Dept Physiol & Biophys, Sao Paulo - Brazil

^[5] Univ Sao Paulo, Inst Biomed Sci, Dept Parasitol, Sao Paulo - Brazil

^[6] Georgetown Univ, Dept Chem & Biochem, Washington, DC - USA

^[7] Georgetown Univ, Dept Cellular & Mol Biol, Washington, DC - USA

^[8] Virginia Tech, Dept Biochem, Blacksburg, VA - USA

^[9] Univ London, St Georges Univ Hosp, Inst Infect & Immun, London - England

^[10] Penn State Univ, Dept Chem & Biochem, State Coll, PA - USA

^[11] Penn State Univ, Dept Mol Biol, State Coll, PA - USA

^[12] Penn State Univ, Ctr Malaria Res, State Coll, PA - USA

^[13] Univ Sao Paulo, Sch Pharmaceut Sci, Dept Clin & Toxicol Anal, Sao Paulo - Brazil

^[14] Columbia Univ, Dept Med, Med Ctr, Div Infect Dis, New York, NY 10027 - USA

• Tipo de documento: Artigo Científico
• Fonte: SCIENTIFIC REPORTS; v. 8, SEP 11 2018.
• Citações Web of Science: 3

Resumo

Plasmodium falciparum multidrug resistance constitutes a major obstacle to the global malaria elimination campaign. Specific mutations in the Plasmodium falciparum chloroquine resistance transporter (PfCRT) mediate resistance to the 4-aminoquinoline drug chloroquine and impact parasite susceptibility to several partner agents used in current artemisinin-based combination therapies, including amodiaquine. By examining gene-edited parasites, we report that the ability of the widespread Dd2 PfCRT isoform to mediate chloroquine and amodiaquine resistance is substantially reduced by the addition of the PfCRT L272F mutation, which arose under blasticidin selection. We also provide evidence that L272F confers a significant fitness cost to asexual blood stage parasites. Studies with amino acid-restricted media identify this mutant as a methionine auxotroph. Metabolomic analysis also reveals an accumulation of short, hemoglobin-derived peptides in the Dd2 + L272F and Dd2 isoforms, compared with parasites expressing wild-type PfCRT. Physiologic studies with the ionophores monensin and nigericin support an impact of PfCRT isoforms on Ca2+ release, with substantially reduced Ca2+ levels observed in Dd2 + L272F parasites. Our data reveal a central role for PfCRT in regulating hemoglobin catabolism, amino acid availability, and ionic balance in P. falciparum, in addition to its role in determining parasite susceptibility to heme-binding 4-aminoquinoline drugs. (AU)

• Processo FAPESP: 11/51295-5 - Genômica funcional em Plasmodium
• Beneficiário: Célia Regina da Silva Garcia
• Modalidade de apoio: Auxílio à Pesquisa - Temático