Discovering host/parasite interactions during larval development of gastrointestinal nematodes

点击翻译按钮获取中文摘要

As the human population continues to grow, pressures on the world's food supplies increase. To meet these needs, dietary protein is going to disproportionately come from meat products. Worldwide, gastrointestinal nematodes (GINs), parasitic roundworms, are one of the greatest production-limiting factors facing livestock. While death is uncommon, hosts are significantly and negatively affected by GIN infection (e.g. anemia, lack of weight gain). GINs are ubiquitous in Canadian livestock and current approaches to control them are unsustainable. The negative impact of GINs to Canada's livestock industry is estimated in the hundreds of millions of dollars annually in lost production and poor animal health. To develop new disease management strategies, we urgently need a better understanding of the immune response to identify the key factors which promote parasite clearance. My research program is focused on discovering how GINs establish successful infections. My study system is Heligmosomoides polygyrus (Hp), a highly prevalent parasite of rodents and a model for GINs of livestock. When Hp larvae are ingested, they enter the intestinal tissue and develop within. Adults emerge days later and remain in the intestinal tract. Immune responses to nematodes like Hp are well described in traditional laboratory models but results often contradict field data. I have developed two grazing models of Hp infection in mice to simulate cattle infection on pasture. My program seeks to discover the mechanisms that underlie why host immunity fails to clear parasites in these models which reflect more natural settings. With this NSERC Discovery Grant, we will focus on early infection events and determine how they influence infection dynamics and outcome. We are experts in the immunological assays and in vivo models we have optimised for use in chronic infections. We will also incorporate transcriptomic analyses (bulk and single cell RNAseq) and newly developed cellular in vitro 3D assays (organoid cultures) pertinent to understanding our new focus on early infection events. We will identify the mechanisms through which Hp larvae interact with their murine host and understand how these impact host/parasite dynamics. This project will create a new relevant in vitro system to study livestock parasites and provide new knowledge on the still relatively unknown topic of GIN larval development and its impact on parasite clearance. This work will be the foundation for biotechnological advances developing `immune boosters' in livestock to promote parasite clearance and informing selective breeding programs on the immune parameters necessary for parasite resistance. This is of direct benefit to the economy, as the total failure of the current drugs will likely cost the Canadian livestock industry one billion Canadian dollars each year. Our results will be an important step to understanding and improving animal health.