Malaria Parasite Development, Drug Resistance, Pathogenesis, and Genomics

点击翻译按钮获取中文摘要

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.