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, genetics, and computational approaches to make discoveries that improve our understanding of parasite biology and host-parasite interactions, as well as our ability to treat parasitic infections. This includes identifying new targets for drug discovery, elucidating of mechanisms of drug resistance, and developing new tools for parasite manipulation and phenotypic screening. We directly study human and animal parasites, including mosquito-borne filarial nematodes, soil-transmitted nematodes, and snail-transmitted blood flukes. To complement these efforts, we leverage the powerful model organism Caenorhabditis elegans. Summaries of active projects are provided below.

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 secretory processes involved in host communication, invasion and migration through host tissues, and neuromuscular and feeding behaviors. We have developed in vivo and in vitro assays to associate specific receptors with phenotypes that can be targetted to prevent or disrupt disease, and to express and screen these receptors in heterologous platforms. Whole-organism strategies: in parallel, we work to develop multivariate whole-parasite screening approaches to define "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