Parasitic diseases exact a massive toll on global public health. Malaria parasites cause 219 million cases of disease and >600,000 deaths annually, while helminth infections are responsible for ~85% of the burden from neglected tropical diseases. This project focuses on two parasitic disease, namely malaria and filariasis. The two diseases represent 15% of the total disease burden imposed by parasitic diseases with malaria being a major cause of death and filariasis being a major cause of disability. We are using high-throughput technologies to study host-pathogen interactions in the high-priority parasitic pathogens, Plasmodium falciparum and Brugia malayi, to study drug resistance, identify novel drug targets, and better define the genomics of protective immunity in both pathogen and host. These studies will result in new tools and strategies for surveillance, prevention, and treatment of malaria and filariasis.
MALARIA. Emerging drug resistant malaria and the potential emergence of "vaccine resistant malaria" threaten to reverse progress that has been made against this disease and derail nascent malaria elimination efforts. We are applying genomic science to two high-priority research goals in support of malaria eradication: 1) develop tools for surveillance of artemisinin-resistant malaria by identifying genetic loci encoding this phenotype; 2) characterize genome-wide Plasmodium diversity with respect to key vaccine antigens in preparation for studies of strain-specific efficacy of a whole organism sporozoite vaccine.
Drug resistance. We will investigate the basis of artemisinin-resistant Plasmodium falciparum (Pf) malaria. Using clinical samples collected in Cambodia, the focus of emerging artemisinin-resistance, we will generate a panel of geographically informative SNPs in the Pf genome, and determine critical patterns of gene flow in the region that can be used to guide containment strategies. Culture adaptation of some of these isolates will be used to identify genetic loci which may complement or act synergistically with mutations in the kelch protein K13, contributing to resistance to artemisinin.
Genomics and Immunity. We will identify loci in host and parasite genomes associated with protective immunity against Pf and characterize genetic variation in populations where a whole organism vaccine will be tested. Using PBMCs collected from children in endemic areas, we will identify differences in cell-mediated immunity in children susceptible to, and protected against, clinical malaria throughout a malaria season. Differences in expression of immunity-related genes will be investigated. We will use clinical isolates of Pf from different epidemiologic settings where a whole-organism malaria vaccine will be tested to characterize Pf genetic diversity, in preparation for evaluating strain-specific vaccine efficacy. Haplotype prevalence and statistics that reflect immune system-driven selection will be estimated for leading vaccine candidates and novel candidates resulting from the immunological studies.
FILARIASIS. Doxycycline is a promising new treatment that can target the adult filarial nematodes, but more alternatives are needed. We are applying genomic techniques and RNAi to identify and characterize drug candidates targeting unique, essential features of this nematode.
Drug targets. We will identify novel, putative filarial drug targets using genome/transcriptome data and examine their functionality and essentiality with RNAi. Whole genome sequence data will be generated from clinical specimens and laboratory lines to characterize Brugia genomic diversity. Transcriptomics and microRNA sequencing experiments will inform our understanding of the molecular basis of the unique biology of mammalian filarial nematodes as well as the interplay between the nematode and its Wolbachia endosymbiont. Novel drug targets will be examined using RNAi after being identified in the genomic and transcriptomic data collected.