Mechanisms of parasitic behavior manipulation in a model host

/Abstract Parasites that hijack the behavior of their animal hosts are incredible neuroscientists. Our proposed research seeks to understand the mechanisms by which the fungus Entomophthora muscae manipulates behavior in its host, the fruit fly Drosophila melanogaster. Broadly, we aim to decode the fungal triggers and fly neural targets involved in behavior manipulation, enhancing our understanding of neural circuitry and its vulnerabilities. Specifically, we seek to identify and characterize the fungal genes responsible for inducing E. muscae summiting behavior (wherein infected flies are driven to climb), understand the molecular cues that trigger flies to summit, determine the necessity of central nervous system invasion by the fungus for driving summiting, and pinpoint which neurons in the fly are directly influenced during this manipulation and how they are impacted. Our innovative approach integrates techniques across neurobiology, genetics, and microbiology, allowing us to uncover "natural" solutions to neuronal circuit manipulation. Utilizing the extensive Drosophila genetic toolkit and modern molecular approaches, we will employ real-time behavioral classification, single-cell mRNA sequencing, and metabolomics to uncover the molecular, genetic, and neural circuit underpinnings of fungal-induced behaviors. Additionally, our work seeks to establish transgenic access to E. muscae and push the field of neuroparasitology beyond correlative studies and into the realm of causal mechanisms between parasite genes and host behavior. Our work offers a fresh perspective on host-parasite interactions, revealing how E. muscae achieves its behavioral influence and providing a unique lens through which to view neural circuit modulation. The outcomes of this research could uncover novel insights into neural circuit functionality and identify new fungal natural products with potential therapeutic applications. Our long-term vision for this work is to set the foundation for broader comparative studies that will enrich our understanding of the evolution of “zombie” parasites and inform how many ways a brain can make a behavior. Project Number: 1R35GM162552-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Carolyn Elya | Institution: HARVARD UNIVERSITY, CAMBRIDGE, MA | Award Amount: $463,375 | Activity Code: R35 | Study Section: Maximizing Investigators' Research Award C Study Section[MRAC] View on NIH RePORTER: https://reporter.nih.gov/project-details/11271314