In the year between 2012-2013, we focused on three major research area: 1) screening and characterizing drugs for combination therapy and transmission blocking;2) studying molecular mechanisms of malaria pathogenesis using Plasmodium yoelii/mouse model;3) molecular basis of an oocyst development defect. We have completed and published the work characterizing a group of compounds that can block malaria parasite transmission (Eastman et al 2013, AAC 57, 425). In collaboration with scientists in NCATS, we are performing large-scale screening of drug combinations. Promising drug combinations have been identified. We are also evaluating the effect of Ca++ and Na+ channel blockers on parasite response to artemisinin. Using rodent malaria parasite P. yoelii, we have made good progresses in studying parasite-host interaction in several directions: 1) We continue to evaluate candidate genes in the loci linked to host cytokine/chemokine response. One of the candidate genes has been shown to affect parasite growth after allelic replacement. 2) We showed that type I interferon (IFN-I) played an important role in controlling parasitemia of rodent malaria parasite Plasmodium yoelii nigeriensis N67. We also demonstrated that the RNA polymerase III and MDA5 mediated signaling contributed to the elevated IFN-I response. A manuscript from this work has been submitted. 3) We developed and tested a microarray platform for genotyping P. yoelii genome. We showed that the array was highly reliable and accurate in calling parasite genotype. A manuscript from this work has been submitted. 4) We have linked an oocyst development defect to a locus on chromosome 6 of P. yoelii and are testing candidate genes in the locus. 5) We have performed a genome-wide linkage analysis on host response to infection of progeny from a genetic cross and identified hundreds of parasite genetic loci linked to responses of many host genes. 6) We performed several additional crosses of P. y. negeriensis N67C and P. y. yoelii YM and have obtained 52 progeny. The genotypes and phenotypes of these progeny are being characterized. 7) We have also crossed P. berghei ANNA and P. berghei NK165 and obtained several progeny to identify genes linked to cerebral malaria. Finally, we are also studying the molecular mechanism of apoptosis and necroptosis after P. yoelii infection. Understanding the molecular mechanism of host-parasite interaction will allow development of effective measures for controlling parasite development and the disease it causes.

Project Start
Project End
Budget Start
Budget End
Support Year
13
Fiscal Year
2013
Total Cost
$1,242,271
Indirect Cost
City
State
Country
Zip Code
Eastman, Richard T; Khine, Pwint; Huang, Ruili et al. (2016) PfCRT and PfMDR1 modulate interactions of artemisinin derivatives and ion channel blockers. Sci Rep 6:25379
Li, Jian; Cai, Baowei; Qi, Yanwei et al. (2016) UTR introns, antisense RNA and differentially spliced transcripts between Plasmodium yoelii subspecies. Malar J 15:30
Zhao, Wenting; Liu, Jianwen; Xu, Ruixue et al. (2015) The Gametocytes of Leucocytozoon sabrazesi Infect Chicken Thrombocytes, Not Other Blood Cells. PLoS One 10:e0133478
Askenase, Michael H; Han, Seong-Ji; Byrd, Allyson L et al. (2015) Bone-Marrow-Resident NK Cells Prime Monocytes for Regulatory Function during Infection. Immunity 42:1130-42
Huang, Bo; Deng, Changsheng; Yang, Tao et al. (2015) Polymorphisms of the artemisinin resistant marker (K13) in Plasmodium falciparum parasite populations of Grande Comore Island 10 years after artemisinin combination therapy. Parasit Vectors 8:634
Qi, Yanwei; Zhu, Feng; Eastman, Richard T et al. (2015) Regulation of Plasmodium yoelii oocyst development by strain- and stage-specific small-subunit rRNA. MBio 6:e00117
Su, Xin-Zhuan; Miller, Louis H (2015) The discovery of artemisinin and the Nobel Prize in Physiology or Medicine. Sci China Life Sci 58:1175-9
Wu, Jian; Cai, Baowei; Sun, Wenxiang et al. (2015) Genome-wide Analysis of Host-Plasmodium yoelii Interactions Reveals Regulators of the Type I Interferon Response. Cell Rep 12:661-72
Zhao, Wenting; Cai, Baowei; Qi, Yanwei et al. (2014) Multi-strain infections and 'relapse' of Leucocytozoon sabrazesi gametocytes in domestic chickens in southern China. PLoS One 9:e94877
Ojo, Kayode K; Eastman, Richard T; Vidadala, Ramasubbarao et al. (2014) A specific inhibitor of PfCDPK4 blocks malaria transmission: chemical-genetic validation. J Infect Dis 209:275-84

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