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 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 Discovery at the Host-Parasite Interface:Driven by the need for new antiparasitics, we mix 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. We apply 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, invasion and migration through host tissues, and neuromuscular 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. 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. We are leveraging these high-throughput pipelines across a range of helminths for chemogenomic profiling and scaled natural product screens in an evolutionary and ecological framework.
Anthelmintic Resistance and Action:Motivated by the threat of anthelmintic resistance in parasite populations, we work to resolve the mechanisms by which existing antiparasitics act and to uncover genes and genetic variation that control drug sensitivity in filarial and soil-transmitted helminths. This work involves the expansion of phenotypes used to capture parasite drug responses, 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 carrying out 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.
Field Study of Neglected Pathogens:We have established a field program through the Colombia-Wisconsin One Health Consortium (CWOHC) focused on understudied insect and soil-transmitted parasites. We have strong reason to believe that filarial nematodes of the genus Mansonella are associated with underappreciated clinical consequences and may alter host susceptibility to other pathogens. We have initiated studies to map filarial disease prevalence in the Colombian Amazon, survey co-infections (viral, parasitic, and bacterial), and validate molecular diagnostics approaches that may eventually be deployed in field settings. These activities are seeding new lines of work and provide us valuable opportunities to engage with colleagues who live in endemic areas.
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 improve the quality of genomes and gene annotations, deliver novel inferences from spatial and single-cell transcriptomic data, and 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.