Date of Award
Spring 2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Microbiology
First Advisor
Palm, Noah
Abstract
Our microbiota, the trillions of microbes that constitutively colonize every outward-facing surface of our bodies, have diverse impacts on human physiology, yet the molecular bases for these effects remain mostly unknown. Classical pathogens often invade host tissues and modulate immune responses through interactions with human extracellular and secreted proteins (the ‘exoproteome’). Commensal microbes may also facilitate niche colonization and shape host biology by engaging host exoproteins; however, direct microbiota-exoproteome interactions remain largely unexplored. We developed and validated a novel technology, BActerial Selection to Elucidate Host-microbe Interactions in high Throughput (BASEHIT), that enables proteome-scale assessment of human exoproteome-microbiome interactions. Using BASEHIT, we interrogated >1.7 million potential interactions between 519 human-associated bacterial strains from diverse phylogenies and tissues of origin and 3,324 human exoproteins. The resulting interactome revealed an extensive network of transkingdom connectivity consisting of thousands of previously undescribed host-microbe interactions involving 383 strains and 651 host proteins. Specific binding patterns within this network implied underlying biological logic: for example, conspecific strains exhibited shared exoprotein-binding patterns, and individual tissue isolates uniquely bound tissue-specific exoproteins. Furthermore, we observed dozens of unique and often strain-specific interactions with potential roles in niche colonization, tissue remodeling, and immunomodulation, and found that strains with differing host interaction profiles had divergent interactions with host cells in vitro and impacts on the host immune system in vivo. Overall, these studies expose a previously unexplored landscape of molecular-level host-microbiota interactions that may underlie causal impacts of indigenous microbes on human health and disease.
Recommended Citation
Sonnert, Nicole, "Uncovering Transkingdom Connectivity Through Mapping Host-Microbiota Interactions" (2024). Yale Graduate School of Arts and Sciences Dissertations. 1313.
https://elischolar.library.yale.edu/gsas_dissertations/1313
