EDGE FGT: Tools for host-microbiome protein-protein interaction discovery

Cornell University, Ithaca NY

Investigators

Abstract

Host-microbe interactions are crucial for normal physiological and immune system development and substantial evidence now links these interactions with a wide range of host phenotypes, including promoting drought tolerance in plants, olfactory communication linked to preening in birds, athletic ability in humans, and mating preferences in fruit flies. Highly specific microbe-associated molecular patterns (MAMPs), many of which involve proteins, directly signal with pattern recognition receptors present on the host epithelium and in host immune tissue, directly modulating host phenotypes. Although pathogen protein-protein interactions (PPIs) have been well studied, the study of PPIs between hosts and their endogenous microbiota is surprisingly lacking. Among the best-studied examples are interactions with animals’ toll-like receptors or plants’ flagellin-sensitive receptor, but other intriguing examples have emerged in recent years, such as mimicry of E3 ubiquitin ligases in the plant pathogen Pseudomonas syringae and commensal-derived proteins that can degrade host metabolic hormones. High-throughput PPI studies have generated substantial experimental data in recent years, yet only a small fraction represents inter-species interactions and this fraction is largely dominated by host-pathogen interactions, with non-human species noticeably lacking. Our goal is to develop tools for PPI discovery and to engage students in opportunities to expand their bioinformatic skills. Within this grant, we will establish sequencing-compatible ultra-high-throughput experimental screening approaches for the discovery of host-microbiome PPIs. Our platforms enable screening the roughly 10^8 possible interactions between a complex host and its microbiome. We will pilot and validate our methods with human and rhizome microbiomes. All resources will be made publicly available and training will be provided. In parallel, we will develop a set of computational tools to assign host-microbiome PPI-based functions. We aim to expand and integrate our PPI inference methods and build a platform that leverages inferred as well as experimentally-verified PPIs and microbiome composition data to allow researchers to investigate the host-microbiome interactome of any plant or animal host. Additionally, to help broaden the overall interest and expose students to computational biology, we will launch a series of bioinformatics hackathon centered around host-microbe interactions. Students are drawn to hackathons and, in our experience, they have served as a great means of exposure for students historically underrepresented in computational biology. Our annual hackathons will center on protein structure-inspired projects for students to engage in a low-stress, fun and inclusive environment. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.