WHAT WE DO
Malaria is a major public health concern, with about 3.2 billion people at risk worldwide and about half a million deaths annually. The most lethal, causative organism of the disease, Plasmodium falciparum, has acquired resistance to every antimalarial drug on the market; therefore, there is an urgent need to understand more about the development of resistance.
The life cycle of the parasite begins with the transmission of sporozoites from mosquitoes to humans. This parasite stage travels to the liver and silently replicates itself. After several rounds, merozoites are released from the liver cells and go on to infect red blood cells. Here, the parasites cyclically rupture and re-invade red blood cells, causing the repeated fevers of malaria. Most drugs target this stage of the life cycle. The high numbers of parasites and strong selective pressures at this stage are conducive to the rapid development of resistance.
Research in the Guler Malaria Lab focuses on the blood stage of P. falciparum. We are working to understand more about how the parasite initiates the development of resistance and how it adapts to the resistant state. We are also interested in developing new tools to help track antimalarial resistance across the world. These projects, as well as the methods that we use, are described in more detail below.
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The Guler Malaria Lab at UVA considers Divesity and Inclusion to be an important part of our work. Please visist our DEI Statement here.
RESISTANCE INITIATION
Copy number variations (CNVs) are associated with many resistance phenotypes, and potentially act as an essential first step that initiates beneficial genetic change. We aim to provide mechanistic insight into how CNVs are generated and ultimately contribute to resistance.
Techniques used in these studies: CHEF, Southern Blotting, Digital Droplet PCR, Geneious, In Vitro Drug Selections
METABOLIC ADAPTATION
Some genetic alterations that arise during antimalarial exposure drive metabolic adaptation in the parasite. By employing metabolite profiling paired with computational modeling to investigate these slight adjustments, we aim to reveal unique pathways that enhance parasite survival.
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Techniques used in these studies: Whole-cell and Serum Metabolomics, Constraint-based Reconstructions, Flux Balance Analysis, Network-based Expression Analysis, Random Forest Analysis, Ring Stage Survival Assays, Westerns, Flow Cytometry
MOLECULAR DIAGNOSTICS
To facilitate antimalarial resistance surveillance, we are developing new tools for the detection of resistance markers on both a small and large scale. Importantly, we collaborate with researchers in malaria-endemic countries to implement these methods, build research capacity, and potentially inform local treatment regimens.
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Techniques used in these studies: High Resolution Melt Analysis, Taqman Probe-based Quantitative PCR