Discovering novel genes involved in immune evasion and drug resistance in the human malaria parasite, Plasmodium falciparum, is of critical importance to global health. Such knowledge may assist in the development of new effective vaccines and in the appropriate use of antimalarial drugs. By performing a full-genome scan of allelic variability in 14 field and laboratory strains of P. falciparum, we comprehensively identified approximately 500 genes evolving at higher than neutral rates. The majority of the most variable genes have paralogs within the P. falciparum genome and may be subject to a different evolutionary clock than those without. The group of 211 variable genes without paralogs contains most known immunogens and a few drug targets, consistent with the idea that the human immune system and drug use is driving parasite evolution. We also reveal gene-amplification events including one surrounding pfmdr1, the P. falciparum multidrug-resistance gene, and a previously uncharacterized amplification centered around the P. falciparum GTP cyclohydrolase gene, the first enzyme in the folate biosynthesis pathway. Although GTP cyclohydrolase is not the known target of any current drugs, downstream members of the pathway are targeted by several widely used antimalarials. We speculate that an amplification of the GTP cyclohydrolase enzyme in the folate biosynthesis pathway may increase flux through this pathway and facilitate parasite resistance to antifolate drugs.

Identifying how small molecules act to kill malaria parasites can lead to new chemically validated targets. By pressuring Plasmodium falciparum asexual blood stage parasites with three novel structurally-unrelated antimalarial compounds (MMV665924, MMV019719 and MMV897615), and performing whole-genome sequence analysis on resistant parasite lines, we identify multiple mutations in the P. falciparum acyl-CoA synthetase (ACS) genes PfACS10 (PF3D7_0525100, M300I, A268D/V, F427L) and PfACS11 (PF3D7_1238800, F387V, D648Y, and E668K). Allelic replacement and thermal proteome profiling validates PfACS10 as a target of these compounds. We demonstrate that this protein is essential for parasite growth by conditional knockdown and observe increased compound susceptibility upon reduced expression. Inhibition of PfACS10 leads to a reduction in triacylglycerols and a buildup of its lipid precursors, providing key insights into its function. Analysis of the PfACS11 gene and its mutations point to a role in mediating resistance via decreased protein stability.

The Madagascar Health and Environmental Research-Antongil (MAHERY-Antongil) study cohort was set up in September 2015 to assess the nutritional value of seafood for the coastal Malagasy population living along Antongil Bay in northeastern Madagascar. Over 28 months of surveillance, we aimed to understand the relationships among different marine resource governance models, local people's fish catch, the consumption of seafood, and nutritional status. In the Antongil Bay, fisheries governance takes three general forms: traditional management, marine national parks, and co-management. Traditional management involves little to no involvement by the national government or non-governmental organizations, and focuses on culturally accepted Malagasy community practices. Co-management and marine national parks involve management support from either an non-govermental organization (NGO) or the national government. Five communities of varying governance strategies were enrolled into the study including 225 households and 1031 individuals whose diets, resource acquisition strategies, fisheries and agricultural practices, and other social, demographic and economic indicators were measured over the span of 3 years. Clinical visits with each individual were conducted at two points during the study to measure disease and nutritional status. By analyzing differences in fish catch arising from variation in governance (in addition to intra-annual seasonal changes and minor inter-annual changes), the project will allow us to calculate the public health value of sustainable fisheries management approaches for local populations. There is hope that coastal zones that are managed sustainably can increase the productivity of fisheries, increasing the catch of seafood products for poor, undernourished populations.

The Plasmodium falciparum parasite's ability to adapt to environmental pressures, such as the human immune system and antimalarial drugs, makes malaria an enduring burden to public health. Understanding the genetic basis of these adaptations is critical to intervening successfully against malaria. To that end, we created a high-density genotyping array that assays over 17,000 single nucleotide polymorphisms (∼ 1 SNP/kb), and applied it to 57 culture-adapted parasites from three continents. We characterized genome-wide genetic diversity within and between populations and identified numerous loci with signals of natural selection, suggesting their role in recent adaptation. In addition, we performed a genome-wide association study (GWAS), searching for loci correlated with resistance to thirteen antimalarials; we detected both known and novel resistance loci, including a new halofantrine resistance locus, PF10_0355. Through functional testing we demonstrated that PF10_0355 overexpression decreases sensitivity to halofantrine, mefloquine, and lumefantrine, but not to structurally unrelated antimalarials, and that increased gene copy number mediates resistance. Our GWAS and follow-on functional validation demonstrate the potential of genome-wide studies to elucidate functionally important loci in the malaria parasite genome.