Neglected Diseases (NTDs) caused by parasitic worms (helminths) impose a debilitating health and economic burden throughout much of the world. These global diseases of poverty infect over 1.5 billion humans and exert their damage through a wide range of species-specific clinical manifestations. Parasitic diseases are also a major challenge to animal and plant health. The central ambition of our laboratory is to combine molecular biology, genetics, and computational approaches to make discoveries that improve our understanding of parasite biology and our ability to treat parasitic infections. This includes the identification of new targets for drug discovery, the elucidation of mechanisms of drug resistance, and the development of new tools for parasite manipulation and phenotypic screening. Our work involves the direct study of human and animal parasites, including the mosquito-borne nematodes Brugia malayi and Dirofilaria immitis, and the snail-transmitted blood fluke Schistosoma mansoni. To complement these efforts, we leverage the power of the model nematode Caenorhabditis elegans. We strive to place our work in the context of a growing appreciation for parasite genetic diversity. Summaries of current research projects are outlined on this page.
Drug Target Discovery at the Host-Parasite Interface:Driven by the need for new antiparasitics, we mix novel target-based and whole-organism screening approaches in order to validate new drug and vaccine targets and discover candidate antiparasitic compounds to treat parasitic nematodes. Target-based strategies: we apply genomic, reverse genetic, and pharmacological tools to identify cell-surface receptors that mediate critical aspects of the host-parasite interaction. These include parasite receptors that control (1) secretory processes involved in host communication, (2) invasion and migration through host tissues, and (3) neuromuscular and feeding behaviors. We have developed in vivo and in vitro parasite assays to associate specific receptors with phenotypes that can potentially be targetted to prevent or disrupt disease, and to express and characterize these receptor targets in heterologous screening platforms. Whole-organism strategies: in parallel, we work to develop multivariate whole-parasite screening approaches to define and capture "cryptic" phenotypes that serve as useful indicators of in vivo drug efficacy.
Anthelmintic Resistance and Action:Motivated by the threat of anthelmintic resistance in parasite populations, we work to help resolve genes and genetic variation that modulate drug sensitivity in clade III filarial and soil-transmitted parasites. This work involves the localization of drug-responsive targets within parasite cells and tissues, the functional expression of parasite genes in model nematode systems, and introducing and assaying the effects of candidate resistance mutations on drug response.
Determinants of Vector Competence:We are involved in collaborative studies to uncover the genetic and molecular determinants of vector competence for helminth parasites. We are using genetic mapping and transcriptomic approaches to identify the basis for mosquito susceptibility to filarial nematode infection. We are using single-cell and gene editing approaches to understand the immunological basis for snail susceptibility to schistosome infection. These studies will generate basic knowledge of biochemical and innate immune responses in two important disease vector systems, with implications for vector-based control strategies.
Improving Helminth Resources and Tools:To complement our hypothesis-driven work, we are engaged in a number of projects to improve the state of helminth genomic data and the tools available to experimentally manipulate helminth systems. This includes ongoing work to (1) improve the quality of genomes and gene annotations, (2) deliver spatial and single-cell transcriptomic data in nematodes, and (3) adapt and further develop genetic manipulation strategies in parasites and their vectors. These efforts provide us more powerful data and tools to make progress on our core aims.
Current and Past Funding Sources