The generation and maintenance of genetic novelty in helminth populations

Helminths, commonly called parasitic worms, are a group of organisms that exploit an incredibly diverse range of hosts and life history strategies for their persistence across generations. Helminth infections of humans and animals of veterinary importance, such as companion and food-producing animals, are responsible for a significant disease burden in their hosts that causes pain, disability, developmental delay, and in some cases, death around the world. Worldwide, over 1.5 billion people and countless animals are infected with one or more helminth species at any given time. As such, human helminth infections are the target of large-scale mass drug administration campaigns, and in veterinary settings, hundreds of millions of animals are treated with anthelmintic drugs to prevent and/or cure infections. The importance of anthelmintics to treat helminth infections cannot be understated; the discovery and development of ivermectin as an anthelmintic was recognised by a Nobel Prize in Physiology or Medicine in 2015.

The ability of helminths to survive and adapt within or outside their hosts lies in their capacity to generate and maintain significant genetic novelty upon which selection can act, which in turn determines their adaptive potential. Two examples clearly illustrate this adaptive potential: (i) the ability of helminths to parasitise single or multiple host species has arisen from free-living ancestors independently many times throughout their evolutionary history, with different species of helminth exploiting distinct mechanisms to invade and establish in their host, and (ii) widespread and frequent use of anthelmintic drugs to control parasites has rapidly selected for drug-resistant parasites. Only three classes of broad-spectrum anthelmintics are available; in veterinary animals (and particularly in livestock), resistance to all of classes including to multiple classes simultaneously has been documented in many helminths species throughout the world, in as little as a few years after introduction of the drug. In humans, there are increasing concerns that reduced efficacy of these same drugs is evidence of emerging resistance, which threatens to reverse gains from up to 30 years of successful treatment and parasite control. The genetic basis for this adaptation is, however, poorly understood. This major gap in our knowledge, largely due to the high genetic diversity and experimental intractability of most helminth species, limits our ability to understand these processes, which need to be overcome to successfully treat disease and predict outcomes of long-term control programmes.

My work will identify the genetic mechanisms underpinning parasite adaptation. To do so, I will focus initially on the impact drug selection using ivermectin, a vitally important drug in human and animal health, has on the genetic diversity of Haemonchus contortus, a major economically important gastrointestinal parasite of livestock worldwide and a genetically tractable model used for drug discovery, vaccine development, and anthelmintic resistance research. Using a genetic cross between susceptible and ivermectin resistant H. contortus strains to control genetic diversity, together with high-throughput population and single-cell genomic approaches to sample genetic diversity over a multi-year evolution experiment, this research will dissect the interaction between genetic and phenotypic variation, and the impact that selection has on shaping this variation. Further, these data will show their potential for future adaptation, and identify evolutionary constraints that may be exploited for novel control interventions. More broadly, these data will inform practices to improve the health and welfare of animals exposed to parasites like H. contortus, and provide a novel experimental and theoretical framework toward understanding the adaptive potential of genetically intractable helminth species of human and veterinary medical importance

The overall aim of the proposed research is to understand how helminths generate and maintain genetic novelty, and how this novelty is used and changes in response to selection. These poorly understood aspects of helminth evolution will underpin the success or failure of any parasite control strategies in the future. The data and resources generated will inform the mechanisms by which helminths have become successful parasites, demonstrate their potential for future adaptation, and identify evolutionary constraints that may be exploited for novel control interventions.

The primary beneficiaries of this work are academic researchers working on H. contortus and/or related helminth species. In the short-term, these data will allow researchers to identify the context of "where" genes of interest are expressed, "when" during development this takes place, and "how" certain gene variants are used differently throughout the life cycle and in different cells of the parasite. Further, this rich transcriptional data will be incorporated into the H. contortus genome annotation and made available without restriction on the helminth community portal WormBase Parasite; this fine-grained information will not only benefit the H. contortus community, it will also provide very strong experimental evidence for gene annotations in other helminth species, many of which are only computationally predicted, have been poorly annotated, and/or contain no known functions.

In the longer term, the results generated here will impact broader questions related to the sustainable control of helminths that infect humans and animals globally. Over 1.5 billion people worldwide are infected with one or more helminth species at any given time, and countless animals are exposed or infected, such that human helminth infections are the target of large scale mass drug administration campaigns, and in veterinary settings, millions of animals worldwide are prophylactically treated with drugs to prevent and/or cure infection. Resistance to the few drugs available is already widespread in helminths of veterinary animals, while evidence of resistance is emerging in human-infective helminths treated with these same few compounds. New approaches to control these infections and manage resistance to maintain the efficacy of these drugs are desperately needed. The data generated here will inform this goal in a number of ways:
- A comprehensive understanding of the genome diversity at single-cell resolution will likely identify novel targets for alternative means to control the parasite;
- Understanding the relationship between phenotypic and genetic responses to resistance will allow for more precise diagnostic testing of resistance in the field, the detection of which may allow early intervention before there is an impact on human and/or animal health;
- Understanding fitness costs associated with resistant alleles will feed back into refugia-based management strategies that aim to limit the accumulation of resistant alleles;
- Surveillance of helminths using genomic tools will become increasingly common in health programs that aim to characterise, for example, treatment efficacy, transmission dynamics, and population decline toward infection elimination; the theoretical and empirical frameworks developed here will inform the development of such tools to monitor and/or predict change in helminth populations over time using genetic variation.

Finally, the flexibility and extended support that the UKRI Future Leaders Fellowship provides will positively impact my career progression as I establish an independent research group, and research agenda toward understanding aspects of the population biology of helminths using cutting-edge genomics. Further, the research proposed will also provide exciting opportunities for the PDF to receive training and acquisition of new skills that will benefit their career development towards independence.