Metabolic adaptation during helminth infection

Soil transmitted helminths are gastrointestinal parasitic worms which infect approximately 1.5 billion people worldwide. Notably, helminths cause significant morbidities including growth stunting and cognitive impairment but are also associated with a reduced risk of metabolic disease such as type 2 diabetes suggesting that helminth infection modifies host metabolism. Shifts in host metabolism are a common response to infection by pathogens including bacteria (e.g., E. coli), viruses (e.g., influenza) and parasites (e.g., malaria) and these metabolic changes often support specific pathogen resistance mechanisms that limit the detrimental impacts of infection. However, how helminth infection rewires host metabolism and what this means for the anti-helminthic response has largely been neglected. I hypothesise that helminth infection promotes a distinct metabolic program which in turn modifies the bodys response against the parasitic worms but which may also have long-term impacts on metabolic health. To investigate this, I will use a mouse model of helminth infection using the mouse restricted helminth Heligmosomoides polygyrus, which replicates many important aspects of human helminth infections including protection against metabolic disease. My first aim is to understand the specific metabolic adaptations which occur during helminth infection at both a systemic and organ specific level. Initially I will map the trajectory of helminth induced metabolic changes over the course of infection both systemically (blood) and in various tissues including the adipose, liver and gastrointestinal tract. Then I will use genetic and pharmacological interventions to determine the helminth induced signals which drive these metabolic changes. Secondly, I will decipher how helminth induced metabolic changes affect how the host tolerates and responds to infection. I will perturb host metabolism during helminth infection using pharmacological, nutritional or genetic interventions and then assess the anti-helminthic immune response, host tissue function and parasite burden. Finally, to understand how helminth induced metabolic changes affect long term health, juvenile mice will be infected with H. polygyrus and then pharmacologically cured after 4 weeks of infection. Metabolic health will be assessed over several months in the post-infection phase relative to animals which never experienced helminth infection. Altogether, this project proposes the novel concept that helminth induced immune crosstalk with metabolic organs (e.g., adipose tissue, liver and small intestine) modifies systemic metabolism, in turn providing the nutritional cues required for an effective antihelminthic response. This work will identify targets which can be leveraged to limit helminth associated morbidities or to tackle metabolic disease.