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Updated: Jun 30, 2025
High-Throughput Transcriptome Analysis for Investigating Host-Pathogen Interactions
Published on: March 5, 2022
A host-microbiota interactome reveals extensive transkingdom connectivity
Nicole D Sonnert1,2, Connor E Rosen1, Andrew R Ghazi3,4
1Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.
Abstract:
The myriad microorganisms that live in close association with humans have diverse effects on physiology, yet the molecular bases for these impacts remain mostly unknown1-3. Classical pathogens often invade host tissues and modulate immune responses through interactions with human extracellular and secreted proteins (the 'exoproteome'). Commensal microorganisms may also facilitate niche colonization and shape host biology by engaging host exoproteins; however, direct exoproteome-microbiota interactions remain largely unexplored. Here we developed and validated a novel technology, BASEHIT, that enables proteome-scale assessment of human exoproteome-microbiome interactions. Using BASEHIT, we interrogated more than 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-microorganism 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 remodelling and immunomodulation, and found that strains with differing host interaction profiles had divergent interactions with host cells in vitro and effects 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 effects of indigenous microorganisms on human health and disease.
Insights
Researchers mapped millions of interactions between human proteins and bacteria, revealing a vast network of connections. This discovery sheds light on how microbes influence human health and disease at a molecular level.
Area of Science:
- Microbiology
- Human Physiology
- Proteomics
Background:
- Microorganisms profoundly impact human health, but the molecular mechanisms are poorly understood.
- Pathogens and commensals interact with human proteins (exoproteome) to colonize and modulate host biology.
- Direct exoproteome-microbiota interactions are largely unexplored.
Purpose of the Study:
- To develop and validate a novel technology for large-scale assessment of human exoproteome-microbiome interactions.
- To explore the molecular landscape of host-microorganism interactions.
Main Methods:
- Developed and validated BASEHIT (Bacterial-Associated Secretome-Host Interaction Technology).
- Interrogated over 1.7 million potential interactions between 519 bacterial strains and 3,324 human exoproteins.
- Analyzed binding patterns to infer biological logic and functional roles.
Main Results:
- Discovered an extensive interactome of thousands of novel host-microorganism interactions involving 383 bacterial strains and 651 human proteins.
- Observed specific binding patterns correlating with bacterial phylogeny, tissue origin, and exoprotein specificity.
- Identified strain-specific interactions potentially involved in niche colonization, tissue remodeling, and immunomodulation.
Conclusions:
- Exposes a vast, previously uncharacterized network of molecular interactions between the human exoproteome and resident microbiota.
- Demonstrates that distinct microbial interaction profiles correlate with differential host cell and immune system effects.
- Suggests these molecular interactions are fundamental to the role of indigenous microorganisms in human health and disease.
