Development of essential research tools for sustaining global programs for the elimination of human hookworms

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PROJECT SUMMARY/ABSTRACT Hookworm genomes are currently poorly assembled and remain highly fragmented making it impossible to determine changes in the genetic architecture in response to drug treatment, and thus to identify genes associated with drug resistance. The long-term goal is to directly inform global health strategies for mitigating and addressing drug resistance in soil-transmitted helminth (STH) parasites using both clinically applied and genetic/genomic approaches. The overall objective of this application is to develop research tools for sustaining global programs for the elimination of human hookworms as a public health problem. The rationale for this research is that developing an optimal animal model and producing a highly contiguous genome assembly for hookworms will allow identification of resistance loci and the development of new diagnostics to support and sustain global mass drug administration programs (MDA). We propose two specific aims: 1) Develop a novel canine model to support investigations into hookworm biology and genetics and 2) Produce a highly contiguous genome assembly for A. caninum. In the first aim, a novel system for performing single-pair matings of A. caninum hookworms will be developed whereby a pair of male/female immature worms will be placed in a gelatin capsule that will be deposited in the mid-jejunum via endoscopic guided delivery. High levels of polymorphism in nematodes limit the contiguity of genome assemblies, thus we will use this model to produce a new inbred line with reduced polymorphism. For the second aim, inbred worms will serve as the source of genetic material for deep sequencing using long-read sequencing together with short-read approaches to produce a highly contiguous genome assembly. The research proposed in this application is innovative because we will develop an experimentally tractable and natural host model with well-described physiology and biochemistry, making it an excellent translational model for human hookworms. Furthermore, naturally evolved multiple-drug resistant isolates of A. caninum already exist and are readily available, providing the source genetic material to interrogate the genetic loci involved with resistance. Similar biologic resources and a model to exploit them for discovery do not currently exist for human hookworms. The proposed research is significant because it is expected to provide essential resources and improve the technical capability for studying the biology and genetics of drug resistance and other important traits in a largely neglected, but medically relevant pathogen. Ultimately, the resources created in this research will facilitate future investigations to develop the research and diagnostic tools necessary to support and sustain global programs for the elimination of human hookworms as a public health problem. These outcomes are anticipated to have a positive impact on the health and well-being of persons living in hookworm-endemic regions by improving the sustainability of MDA strategies, making it possible to both eliminate disease from STH while minimizing the risks of long-term program failure due to anthelmintic resistance.