In the past year, we continued to study Plasmodium falciparum genome diversity, drug resistance, gene regulation, and virulence using genetic mapping, microarray, gene knockout, genetic crosses, population genetics, and other approaches. The ultimate goals are to relate genetic polymorphisms to parasite biology and to develop novel approaches to control malaria. We have obtained thousands of single nucleotide polymorphisms (SNPs) from 185 culture adapted isolates, tested the parasite responses to seven antimalarial drugs, used genotype/phenotype data in genome wide association analysis, and identified candidate genes associated with parasite responses to mefloquine, dihydroartemisinin, and other drugs. We upgraded our 3.5k SNP typing array to include 8000 SNPs for mapping genes at higher resolution and have made the array available to the malaria community. We have started functionally testing some of the candidate genes identified from this study. Last year, we initiated a project to systematically characterize parasite differential response to thousands of chemical compounds and have collected hundreds of differential chemical phenotypes (DCPs). We have now tested the DCP compounds in 70 progeny of genetic crosses and have identified many loci that are linked to parasite responses to the DCPs. We have also screened >60 field parasite isolates against a large number of drugs and identified drugs that can kill chloroquine resistant parasites in vitro. We have been developing a genetic map for Plasmodium yoelii to study disease phenotypes. Disease phenotypes are the results of parasite and host interactions. Use of inbred mice will greatly reduce the influence of host factors on phenotype measurement. We have performed 23 individual genetic cross experiments using three pairs of parasite strains (parents) and obtained 134 independent recombinant progeny from the crosses. A genetic linkage map has been developed after typing the progeny with hundreds of microsatellite markers. Several studies have shown differences in gene expression between pairs of isogenic parasites, but no changes in DNA sequences could be identified. We are interested in relationships between parasite nucleosome position and gene expression in various parasite developmental stages. In collaboration with Dr. Keji Zhao of NIDDK, we obtained nucleosome positions and mRNA sequences from different developmental stages of P. falciparum. Mistakes in predicted gene models and alternatively spliced genes have been discovered. We are in the process of analyzing the sequence data.

Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2010
Total Cost
$1,119,920
Indirect Cost
City
State
Country
Zip Code
Shi, Weikun; Xue, Chunyu; Su, Xin-Zhuan et al. (2018) The roles of galectins in parasitic infections. Acta Trop 177:97-104
Qian, Pengge; Wang, Xu; Yang, Zhenke et al. (2018) A Cas9 transgenic Plasmodium yoelii parasite for efficient gene editing. Mol Biochem Parasitol 222:21-28
Deng, Changsheng; Huang, Bo; Wang, Qi et al. (2018) Large-scale Artemisinin-Piperaquine Mass Drug Administration With or Without Primaquine Dramatically Reduces Malaria in a Highly Endemic Region of Africa. Clin Infect Dis :
Zhang, De-Liang; Wu, Jian; Shah, Binal N et al. (2018) Erythrocytic ferroportin reduces intracellular iron accumulation, hemolysis, and malaria risk. Science 359:1520-1523
Huang, Bo; Tuo, Fei; Liang, Yuan et al. (2018) Temporal changes in genetic diversity of msp-1, msp-2, and msp-3 in Plasmodium falciparum isolates from Grande Comore Island after introduction of ACT. Malar J 17:83
Lam, Nelson Siukei; Long, Xinxin; Su, Xin-Zhuan et al. (2018) Artemisinin and its derivatives in treating helminthic infections beyond schistosomiasis. Pharmacol Res 133:77-100
Loo, Cecilia Shi Ni; Lam, Nelson Siu Kei; Yu, Deying et al. (2017) Artemisinin and its derivatives in treating protozoan infections beyond malaria. Pharmacol Res 117:192-217
Lacerda-Queiroz, Norinne; Riteau, Nicolas; Eastman, Richard T et al. (2017) Mechanism of splenic cell death and host mortality in a Plasmodium yoelii malaria model. Sci Rep 7:10438
Zhang, Cui; Gao, Han; Yang, Zhenke et al. (2017) CRISPR/Cas9 mediated sequential editing of genes critical for ookinete motility in Plasmodium yoelii. Mol Biochem Parasitol 212:1-8
Nair, Sethu C; Xu, Ruixue; Pattaradilokrat, Sittiporn et al. (2017) A Plasmodium yoelii HECT-like E3 ubiquitin ligase regulates parasite growth and virulence. Nat Commun 8:223

Showing the most recent 10 out of 75 publications