Molecular mayhem: Immune modulation and eicosanoid signaling during infection

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Project Summary/Abstract A central aspect of parasitic nematode success and prevalence is their ability to modify host biology, including evade and/or subvert the host’s immune response. In some cases, humans can host thousands of nematode parasites with little to no pathology, yet our understanding of this incredible evasion or suppression of the immune system remains limited. Modulation of host biology and the pathology they cause is largely effected through the release of proteins and small molecules that interact with host cells and tissues. There are hundreds of proteins released in nematode spit during an infection and only a few have been studied in any detail. My lab is focused on understanding host-parasite interactions, with an emphasis on elucidating the molecules that parasites release into the host, characterizing their interaction with host signaling pathways to modulate host biology, and learning from the evolution of the parasite arsenal how to manipulate the immune system. Over the next five years my lab will identify key genetic pathways in lipid-mediated immune signaling and identify molecular host- parasite interactions. Our specific focus will be to 1) establish experimental pipelines for identifying novel parasite-derived proteins and small molecules that modulate host biology, 2) determine the effects of the molecules we identify, beginning with members of the fatty acid- and retinol-binding (FAR) protein family, 3) elucidate molecular interactions between parasite molecules and host pathways, and 4) characterize eicosanoid signaling in Drosophila melanogaster, a genetic model of immunity. A major strategy of my lab's research is to combine in silico, in vitro, and in vivo experimental approaches with an established infection model that leverages our deep understanding of fruit fly biology and its powerful genetics, to reveal not only the binding targets of parasite proteins and molecules in an active infection, but also to define their effect on infection outcomes. Our overall goal is to understand how nematode parasites modify host biology in order to successfully infect them. This includes parasites’ ability to evade and/or suppress host immunity, which is important to human health in at least two ways. First, nematode infections continue to be a major source of global morbidity and mortality, affecting more than 25% of the world’s population. Increasing drug resistance and recurring infections compound this problem. And second, there is mounting evidence that the immunomodulatory effects of nematode infections can dampen or even eliminate the pathologies that define autoimmune disorders such as Crohn’s disease, inflammatory bowel disease, and Celiac disease. Understanding how nematodes suppress the immune system will lead to new treatment and vaccination strategies against nematode infection, and may reveal new avenues for treating autoimmune disorders. We will employ a powerful model system to probe immune modulation by nematodes to identify specific secreted proteins and small molecules as well as the signaling pathways they target to effectively manipulate host immunity.