Plasmodium falciparum: multifaceted resistance to artemisinins

Malaria Journal

Volumn 15, Issue 1, 2016, Pages

  Paloque, Lucie ^a,b   Ramadani, Arba P ^a,b,c   Mercereau Puijalon, Odile ^d   Augereau, Jean Michel ^a,b   Benoit Vical, Françoise ^a,b  

^a LCC LABORATOIRE DE CHIMIE DE COORDINATION   (France)

^b UNIVERSITÉ PAUL SABATIER   (France)

^c GADJAH MADA UNIVERSITY   (Indonesia)

^d INSTITUT PASTEUR   (France)

Author keywords

Artemisinin based combination therapy; Malaria; PfK13; Quiescence; Resistance

Indexed keywords

ANTIMALARIAL AGENT; ARTEMISININ DERIVATIVE; INITIATION FACTOR 2ALPHA; MUTANT PROTEIN; PFK13 PROTEIN; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3 PHOSPHATE; PROTEIN KINASE B; UNCLASSIFIED DRUG;

ANTIMALARIAL DRUG RESISTANCE; APICOPLAST; CELL CYCLE; DNA POLYMORPHISM; DRUG EFFICACY; DRUG POTENCY; FATTY ACID METABOLISM; GENE; GENE ACTIVITY; GENE CONTROL; GENE LOCUS; GENE MUTATION; GENOTYPE; HOST PARASITE INTERACTION; HUMAN; MALARIA FALCIPARUM; MITOCHONDRIAL RESPIRATION; NONHUMAN; OXIDATIVE STRESS; PARASITE CLEARANCE; PARASITE DEVELOPMENT; PFK13 GENE; PHARMACOGENETICS; PHENOTYPE; PLASMODIUM FALCIPARUM; PRACTICE GUIDELINE; PROTEIN DOMAIN; REVIEW; UNFOLDED PROTEIN RESPONSE; BIOLOGICAL MODEL; DRUG EFFECTS; DRUG RESISTANCE; GENETICS; PARASITOLOGY;

ANTIMALARIALS; ARTEMISININS; DRUG RESISTANCE; HUMANS; MALARIA, FALCIPARUM; MODELS, BIOLOGICAL; PLASMODIUM FALCIPARUM;

EID: 84960470369     PISSN: None     EISSN: 14752875     Source Type: Journal    
DOI: 10.1186/s12936-016-1206-9     Document Type: Review

References (102)

1. Nobel price. http://www.nobelprize.org/nobel-prizes/medicine/laureates/2015/. 2015.
2. WHO. Status report on artemisinin and ACT resistance. Geneva: World Health Organization; 2015.
3. Ashley EA, Dhorda M, Fairhurst RM, Amaratunga C, Lim P, Suon S, et al. Spread of artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med. 2014;371:411-23.
4. Duru V, Khim N, Leang R, Kim S, Domergue A, Kloeung N, et al. Plasmodium falciparum dihydroartemisinin-piperaquine failures in Cambodia are associated with mutant K13 parasites presenting high survival rates in novel piperaquine in vitro assays: retrospective and prospective investigations. BMC Med. 2015;13:305.
5. Lubell Y, Dondorp A, Guerin PJ, Drake T, Meek S, Ashley E, et al. Artemisinin resistance-modelling the potential human and economic costs. Malar J. 2014;13:452.
6. Fitch CD. Ferriprotoporphyrin IX, phospholipids, and the antimalarial actions of quinoline drugs. Life Sci. 2004;74:1957-72.
7. Robert A, Benoit-Vical F, Claparols C, Meunier B. The antimalarial drug artemisinin alkylates heme in infected mice. Proc Natl Acad Sci USA. 2005;102:13676-80.
8. Kessl JJ, Meshnick SR, Trumpower BL. Modeling the molecular basis of atovaquone resistance in parasites and pathogenic fungi. Trends Parasitol. 2007;23:494-501.
9. Gregson A, Plowe CV. Mechanisms of resistance of malaria parasites to antifolates. Pharmacol Rev. 2005;57:117-45.
10. Bruce-Chwatt L. Chemotherapy of malaria. Geneva: World Health Organization; 1986. p. 245.
11. Maude RJ, Nguon C, Dondorp AM, White LJ, White NJ. The diminishing returns of atovaquone-proguanil for elimination of Plasmodium falciparum malaria: modelling mass drug administration and treatment. Malar J. 2014;13:380.
12. Durand R, Prendki V, Cailhol J, Hubert V, Ralaimazava P, Massias L, et al. Plasmodium falciparum malaria and atovaquone-proguanil treatment failure. Emerg Infect Dis. 2008;14:320-2.
13. Noedl H, Se Y, Schaecher K, Smith BL, Socheat D, Fukuda MM. Evidence of artemisinin-resistant malaria in western Cambodia. N Engl J Med. 2008;359:2619-20.
14. Noedl H, Socheat D, Satimai W. Artemisinin-resistant malaria in Asia. N Engl J Med. 2009;361:540-1.
15. Dondorp AM, Nosten F, Yi P, Das D, Phyo AP, Tarning J, et al. Artemisinin resistance in Plasmodium falciparum malaria. N Engl J Med. 2009;361:455-67.
16. Phyo AP, Nkhoma S, Stepniewska K, Ashley EA, Nair S, McGready R, et al. Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study. Lancet. 2012;379:1960-6.
17. WHO. Guidelines for the treatment of malaria. Geneva: World Health Organization; 2010.
18. WHO. World malaria report 2014. Geneva: World Health Organization; 2014.
19. Na-Bangchang K, Muhamad P, Ruaengweerayut R, Chaijaroenkul W, Karbwang J. Identification of resistance of Plasmodium falciparum to artesunate-mefloquine combination in an area along the Thai-Myanmar border: integration of clinico-parasitological response, systemic drug exposure, and in vitro parasite sensitivity. Malar J. 2013;12:263.
20. Saunders DL, Vanachayangkul P, Lon C. Dihydroartemisinin-piperaquine failure in Cambodia. N Engl J Med. 2014;371:484-5.
21. Leang R, Taylor WR, Bouth DM, Song L, Tarning J, Char MC, et al. Evidence of Plasmodium falciparum malaria multidrug resistance to artemisinin and piperaquine in Western Cambodia: dihydroartemisinin-Piperaquine open-label multicenter clinical assessment. Antimicrob Agents Chemother. 2015;59:4719-26.
22. Spring MD, Lin JT, Manning JE, Vanachayangkul P, Somethy S, Bun R, et al. Dihydroartemisinin-piperaquine failure associated with a triple mutant including kelch13 C580Y in Cambodia: an observational cohort study. Lancet Infect Dis. 2015;15:683-91.
23. WWARN. Clinical determinants of early parasitological response to ACTs in African patients with uncomplicated falciparum malaria: a literature review and meta-analysis of individual patient data. BMC Med. 2015;13:212.
24. Packard RM. The origins of antimalarial-drug resistance. N Engl J Med. 2014;371:397-9.
25. Smith Gueye C, Newby G, Hwang J, Phillips AA, Whittaker M, MacArthur JR, et al. The challenge of artemisinin resistance can only be met by eliminating Plasmodium falciparum malaria across the Greater Mekong subregion. Malar J. 2014;13:286.
26. Samarasekera U. Countries race to contain resistance to key antimalarial. Lancet. 2009;374:277-80.
27. Brown TS, Jacob CG, Silva JC, Takala-Harrison S, Djimde A, Dondorp AM, et al. Plasmodium falciparum field isolates from areas of repeated emergence of drug resistant malaria show no evidence of hypermutator phenotype. Infect Genet Evol. 2015;30:318-22.
28. Miotto O, Amato R, Ashley EA, MacInnis B, Almagro-Garcia J, Amaratunga C, et al. Genetic architecture of artemisinin-resistant Plasmodium falciparum. Nat Genet. 2015;47:226-34.
29. Khim N, Bouchier C, Ekala MT, Incardona S, Lim P, Legrand E, et al. Countrywide survey shows very high prevalence of Plasmodium falciparum multilocus resistance genotypes in Cambodia. Antimicrob Agents Chemother. 2005;49:3147-52.
30. Anderson TJ, Nair S, Nkhoma S, Williams JT, Imwong M, Yi P, et al. High heritability of malaria parasite clearance rate indicates a genetic basis for artemisinin resistance in western Cambodia. J Infect Dis. 2010;201:1326-30.
31. Witkowski B, Lelievre J, Barragan MJ, Laurent V, Su XZ, Berry A, et al. Increased tolerance to artemisinin in Plasmodium falciparum is mediated by a quiescence mechanism. Antimicrob Agents Chemother. 2010;54:1872-7.
32. Imwong M, Dondorp AM, Nosten F, Yi P, Mungthin M, Hanchana S, et al. Exploring the contribution of candidate genes to Artemisinin resistance in Plasmodium falciparum. Antimicrob Agents Chemother. 2010;54:2886-92.
33. Ariey F, Witkowski B, Amaratunga C, Beghain J, Langlois AC, Khim N, et al. A molecular marker of artemisinin-resistant Plasmodium falciparum malaria. Nature. 2014;505:50-5.
34. Looareesuwan S, Wilairatana P, Viravan C, Vanijanonta S, Pitisuttithum P, Kyle DE. Open randomized trial of oral artemether alone and a sequential combination with mefloquine for acute uncomplicated falciparum malaria. Am J Trop Med Hyg. 1997;56:613-7.
35. Ménard S, Ben Haddou T, Ramadani AP, Ariey F, Iriart X, Beghain J, et al. Induction of multidrug tolerance in Plasmodium falciparum by extended artemisinin pressure. Emerg Infect Dis. 2015;21:1733-41.
36. Ménard D, Khim N, Beghain J, Adegnika A, Alam M, Amodu O et al. A worldwide map of Plasmodium falciparum artemisinin resistance. N Engl J Med. 2016. (in press).
37. Hoshen MB, Na-Bangchang K, Stein WD, Ginsburg H. Mathematical modelling of the chemotherapy of Plasmodium falciparum malaria with artesunate: postulation of 'dormancy', a partial cytostatic effect of the drug, and its implication for treatment regimens. Parasitology. 2000;121:237-46.
38. Daignan-Fornier B, Sagot I. Proliferation/quiescence: the controversial "aller-retour". Cell Div. 2011;6:10.
39. Babbitt SE, Altenhofen L, Cobbold SA, Istvan ES, Fennell C, Doerig C, et al. Plasmodium falciparum responds to amino acid starvation by entering into a hibernatory state. Proc Natl Acad Sci USA. 2012;109:E3278-87.
40. Dembele L, Franetich JF, Lorthiois A, Gego A, Zeeman AM, Kocken CH, et al. Persistence and activation of malaria hypnozoites in long-term primary hepatocyte cultures. Nat Med. 2014;20:307-12.
41. Witkowski B, Khim N, Chim P, Kim S, Ke S, Kloeung N, et al. Reduced artemisinin susceptibility of Plasmodium falciparum ring stages in western Cambodia. Antimicrob Agents Chemother. 2013;57:914-23.
42. Peatey CL, Chavchich M, Chen N, Gresty KJ, Gray KA, Gatton ML, et al. Mitochondrial membrane potential in a small subset of Artemisinin-induced dormant Plasmodium falciparum parasites in vitro. J Infect Dis. 2015;212:426-34.
43. Klonis N, Crespo-Ortiz MP, Bottova I, Abu-Bakar N, Kenny S, Rosenthal PJ, et al. Artemisinin activity against Plasmodium falciparum requires hemoglobin uptake and digestion. Proc Natl Acad Sci USA. 2011;108:11405-10.
44. Dogovski C, Xie SC, Burgio G, Bridgford J, Mok S, McCaw JM, et al. Targeting the cell stress response of Plasmodium falciparum to overcome artemisinin resistance. PLoS Biol. 2015;13:e1002132.
45. Wang J, Zhang CJ, Chia WN, Loh CC, Li Z, Lee YM, et al. Haem-activated promiscuous targeting of artemisinin in Plasmodium falciparum. Nat Commun. 2015;6:10111.
46. Hott A, Casandra D, Sparks KN, Morton LC, Castanares GG, Rutter A, et al. Artemisinin-resistant Plasmodium falciparum parasites exhibit altered patterns of development in infected erythrocytes. Antimicrob Agents Chemother. 2015;59:3156-67.
47. Saralamba S, Pan-Ngum W, Maude RJ, Lee SJ, Tarning J, Lindegardh N, et al. Intrahost modeling of artemisinin resistance in Plasmodium falciparum. Proc Natl Acad Sci USA. 2011;108:397-402.
48. Teuscher F, Gatton ML, Chen N, Peters J, Kyle DE, Cheng Q. Artemisinin-induced dormancy in Plasmodium falciparum: duration, recovery rates, and implications in treatment failure. J Infect Dis. 2010;202:1362-8.
49. Chen N, LaCrue AN, Teuscher F, Waters NC, Gatton ML, Kyle DE, et al. Fatty acid synthesis and pyruvate metabolism pathways remain active in dihydroartemisinin-induced dormant ring stages of Plasmodium falciparum. Antimicrob Agents Chemother. 2014;58:4773-81.
50. Straimer J, Gnadig NF, Witkowski B, Amaratunga C, Duru V, Ramadani AP, et al. Drug resistance. K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates. Science. 2015;347:428-31.
51. Mohon AN, Alam MS, Bayih AG, Folefoc A, Shahinas D, Haque R, et al. Mutations in Plasmodium falciparum K13 propeller gene from Bangladesh (2009-2013). Malar J. 2014;13:431.
52. Huang F, Takala-Harrison S, Jacob CG, Liu H, Sun X, Yang H, et al. A single mutation in K13 predominates in Southern China and is associated with delayed clearance of Plasmodium falciparum following artemisinin treatment. J Infect Dis. 2015;212:1629-35.
53. Takala-Harrison S, Jacob CG, Arze C, Cummings MP, Silva JC, Dondorp AM, et al. Independent emergence of artemisinin resistance mutations among Plasmodium falciparum in Southeast Asia. J Infect Dis. 2015;211:670-9.
54. Nyunt MH, Hlaing T, Oo HW, Tin-Oo LL, Phway HP, Wang B, et al. Molecular assessment of artemisinin resistance markers, polymorphisms in the k13 propeller, and a multidrug-resistance gene in the eastern and western border areas of Myanmar. Clin Infect Dis. 2015;60:1208-15.
55. Amaratunga C, Witkowski B, Dek D, Try V, Khim N, Miotto O, et al. Plasmodium falciparum founder populations in western Cambodia have reduced artemisinin sensitivity in vitro. Antimicrob Agents Chemother. 2014;58:4935-7.
56. Amaratunga C, Witkowski B, Khim N, Menard D, Fairhurst RM. Artemisinin resistance in Plasmodium falciparum. Lancet Infect Dis. 2014;14:449-50.
57. Sibley CH. Understanding artemisinin resistance. Science. 2015;347:373-4.
58. Kamau E, Campino S, Amenga-Etego L, Drury E, Ishengoma D, Johnson K, et al. K13-propeller polymorphisms in Plasmodium falciparum parasites from sub-Saharan Africa. J Infect Dis. 2015;211:1352-5.
59. Taylor SM, Parobek CM, DeConti DK, Kayentao K, Coulibaly SO, Greenwood BM, et al. Absence of putative artemisinin resistance mutations among Plasmodium falciparum in sub-Saharan Africa: a molecular epidemiologic study. J Infect Dis. 2014;211:680-8.
60. Maiga-Ascofare O, May J. Is the A578S Single-Nucleotide Polymorphism in K13-propeller a marker of emerging resistance to artemisinin among Plasmodium falciparum in Africa? J Infect Dis. 2016;213:165-6.
61. Hawkes M, Conroy AL, Opoka RO, Namasopo S, Zhong K, Liles WC, et al. Slow clearance of Plasmodium falciparum in severe pediatric Malaria, Uganda, 2011-2013. Emerg Infect Dis. 2015;21:1237-9.
62. Ghorbal M, Gorman M, Macpherson CR, Martins RM, Scherf A, Lopez-Rubio JJ. Genome editing in the human malaria parasite Plasmodium falciparum using the CRISPR-Cas9 system. Nat Biotechnol. 2014;32:819-21.
63. Fairhurst RM. Understanding artemisinin-resistant malaria: what a difference a year makes. Curr Opin Infect Dis. 2015;28:417-25.
64. Popovici J, Kao S, Eal L, Bin S, Kim S, Menard D. Reduced polymorphism in the Kelch propeller domain in Plasmodium vivax isolates from Cambodia. Antimicrob Agents Chemother. 2015;59:730-3.
65. Adams J, Kelso R, Cooley L. The kelch repeat superfamily of proteins: propellers of cell function. Trends Cell Biol. 2000;10:17-24.
66. Protein Data Bank. Crystal structure analysis of Kelch protein from Plasmodium falciparum. http://www.rcsb.org/pdb/explore/explore.do?structureId=4yy8. 2015.
67. Winzeler EA, Manary MJ. Drug resistance genomics of the antimalarial drug artemisinin. Genome Biol. 2014;15:544.
68. Mbengue A, Bhattacharjee S, Pandharkar T, Liu H, Estiu G, Stahelin RV, et al. A molecular mechanism of artemisinin resistance in Plasmodium falciparum malaria. Nature. 2015;520:683-7.
69. Padmanabhan B, Tong KI, Ohta T, Nakamura Y, Scharlock M, Ohtsuji M, et al. Structural basis for defects of Keap1 activity provoked by its point mutations in lung cancer. Mol Cell. 2006;21:689-700.
70. Boyden LM, Choi M, Choate KA, Nelson-Williams CJ, Farhi A, Toka HR, et al. Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities. Nature. 2012;482:98-102.
71. Morita M, Sanai H, Hiramoto A, Sato A, Hiraoka O, Sakura T, et al. Plasmodium falciparum endoplasmic reticulum-resident calcium binding protein is a possible target of synthetic antimalarial endoperoxides, N-89 and N-251. J Proteome Res. 2012;11:5704-11.
72. Mok S, Ashley EA, Ferreira PE, Zhu L, Lin Z, Yeo T, et al. Population transcriptomics of human malaria parasites reveals the mechanism of artemisinin resistance. Science. 2015;347:431-5.
73. Liu Y, Lok CN, Ko BC, Shum TY, Wong MK, Che CM. Subcellular localization of a fluorescent artemisinin derivative to endoplasmic reticulum. Org Lett. 2010;12:1420-3.
74. Gosline SJ, Nascimento M, McCall LI, Zilberstein D, Thomas DY, Matlashewski G, et al. Intracellular eukaryotic parasites have a distinct unfolded protein response. PLoS One. 2011;6:e19118.
75. Kansanen E, Jyrkkänen H-K, Levonen A-L. Activation of stress signaling pathways by electrophilic oxidized and nitrated lipids. Free Radical Bio Med. 2012;52:973-82.
76. Blaustein M, Perez-Munizaga D, Sanchez MA, Urrutia C, Grande A, Risso G, et al. Modulation of the Akt pathway reveals a novel link with PERK/eIF2alpha, which is relevant during hypoxia. PLoS One. 2013;8:e69668.
77. Zhang M, Fennell C, Ranford-Cartwright L, Sakthivel R, Gueirard P, Meister S, et al. The Plasmodium eukaryotic initiation factor-2alpha kinase IK2 controls the latency of sporozoites in the mosquito salivary glands. J Exp Med. 2010;207:1465-74.
78. Salcedo-Sora JE, Caamano-Gutierrez E, Ward SA, Biagini GA. The proliferating cell hypothesis: a metabolic framework for Plasmodium growth and development. Trends Parasitol. 2014;30:170-5.
79. Botte CY, Yamaryo-Botte Y, Rupasinghe TW, Mullin KA, MacRae JI, Spurck TP, et al. Atypical lipid composition in the purified relict plastid (apicoplast) of malaria parasites. Proc Natl Acad Sci USA. 2013;110:7506-11.
80. Bhattacharjee S, Stahelin RV, Speicher KD, Speicher DW, Haldar K. Endoplasmic reticulum PI(3)P lipid binding targets malaria proteins to the host cell. Cell. 2012;148:201-12.
81. Tawk L, Chicanne G, Dubremetz JF, Richard V, Payrastre B, Vial HJ, et al. Phosphatidylinositol 3-phosphate, an essential lipid in Plasmodium, localizes to the food vacuole membrane and the apicoplast. Eukaryot Cell. 2010;9:1519-30.
82. Kobayashi T, Sato S, Takamiya S, Komaki-Yasuda K, Yano K, Hirata A, et al. Mitochondria and apicoplast of Plasmodium falciparum: behaviour on subcellular fractionation and the implication. Mitochondrion. 2007;7:125-32.
83. Shears MJ, Botte CY, McFadden GI. Fatty acid metabolism in the Plasmodium apicoplast: drugs, doubts and knockouts. Mol Biochem Parasitol. 2015;199:34-50.
84. Ralph SA, van Dooren GG, Waller RF, Crawford MJ, Fraunholz MJ, Foth BJ, et al. Tropical infectious diseases: metabolic maps and functions of the Plasmodium falciparum apicoplast. Nat Rev Microbiol. 2004;2:203-16.
85. St Laurent B, Miller B, Burton TA, Amaratunga C, Men S, Sovannaroth S, et al. Artemisinin-resistant Plasmodium falciparum clinical isolates can infect diverse mosquito vectors of Southeast Asia and Africa. Nat Commun. 2015;6:8614.
86. Wongsrichanalai C, Pickard AL, Wernsdorfer WH, Meshnick SR. Epidemiology of drug-resistant malaria. Lancet Infect Dis. 2002;2:209-18.
87. Witkowski B, Berry A, Benoit-Vical F. Resistance to antimalarial compounds: methods and applications. Drug Resist Updat. 2009;12:42-50.
88. Sanchez CP, Dave A, Stein WD, Lanzer M. Transporters as mediators of drug resistance in Plasmodium falciparum. Int J Parasitol. 2010;40:1109-18.
89. Koenderink JB, Kavishe RA, Rijpma SR, Russel FG. The ABCs of multidrug resistance in malaria. Trends Parasitol. 2010;26:440-6.
90. Ibraheem ZO, Abd Majid R, Noor SM, Sedik HM, Basir R. Role of different Pfcrt and Pfmdr-1 mutations in conferring resistance to antimalaria drugs in Plasmodium falciparum. Malar Res Treat. 2014;2014:950424.
91. Summers RL, Nash MN, Martin RE. Know your enemy: understanding the role of PfCRT in drug resistance could lead to new antimalarial tactics. Cell Mol Life Sci. 2012;69:1967-95.
92. Setthaudom C, Tan-ariya P, Sitthichot N, Khositnithikul R, Suwandittakul N, Leelayoova S, et al. Role of Plasmodium falciparum chloroquine resistance transporter and multidrug resistance 1 genes on in vitro chloroquine resistance in isolates of Plasmodium falciparum from Thailand. Am J Trop Med Hyg. 2011;85:606-11.
93. Price RN, Uhlemann AC, Brockman A, McGready R, Ashley E, Phaipun L, et al. Mefloquine resistance in Plasmodium falciparum and increased pfmdr1 gene copy number. Lancet. 2004;364:438-47.
94. Ubben D, Poll EM. MMV in partnership: the Eurartesim(R) experience. Malar J. 2013;12:211.
95. Ke H, Lewis IA, Morrisey JM, McLean KJ, Ganesan SM, Painter HJ, et al. Genetic investigation of tricarboxylic acid metabolism during the Plasmodium falciparum life cycle. Cell Rep. 2015;11:164-74.
96. Kansanen E, Kuosmanen SM, Leinonen H, Levonen AL. The Keap1-Nrf2 pathway: mechanisms of activation and dysregulation in cancer. Redox Biol. 2013;1:45-9.
97. Nakaso K, Yano H, Fukuhara Y, Takeshima T, Wada-Isoe K, Nakashima K. PI3K is a key molecule in the Nrf2-mediated regulation of antioxidative proteins by hemin in human neuroblastoma cells. FEBS Lett. 2003;546:181-4.
98. Raven JF, Koromilas AE. PERK and PKR: old kinases learn new tricks. Cell Cycle. 2008;7:1146-50.
99. Fennell C, Babbitt S, Russo I, Wilkes J, Ranford-Cartwright L, Goldberg DE, et al. PfeIK1, a eukaryotic initiation factor 2alpha kinase of the human malaria parasite Plasmodium falciparum, regulates stress-response to amino-acid starvation. Malar J. 2009;8:99.
100. Zhang M, Mishra S, Sakthivel R, Rojas M, Ranjan R, Sullivan WJ Jr, et al. PK4, a eukaryotic initiation factor 2alpha(eIF2alpha) kinase, is essential for the development of the erythrocytic cycle of Plasmodium. Proc Natl Acad Sci USA. 2012;109:3956-61.
101. Chaubey S, Grover M, Tatu U. Endoplasmic reticulum stress triggers gametocytogenesis in the malaria parasite. J Biol Chem. 2014;289:16662-74.
102. Doerig C, Endicott J, Chakrabarti D. Cyclin-dependent kinase homologues of Plasmodium falciparum. Int J Parasitol. 2002;32:1575-85.