Individual Host Variation in Single-cell Responses to Enteroaggregative Escherichia coli Infection Modeled with Human...

Area of Science:

• Microbiology
• Immunology
• Genetics

Background:

• Enteroaggregative Escherichia coli (EAEC) causes global diarrhea, with varied patient outcomes.
• Host genetic and cellular factors, not just pathogen virulence, influence EAEC disease severity.
• Understanding host-driven disease heterogeneity is crucial for effective treatment.

Purpose of the Study:

• To investigate donor-specific host responses to EAEC infection at the single-cell level.
• To explore the role of intrinsic host cellular composition in EAEC susceptibility.
• To establish human colon organoids as a model for studying infectious disease heterogeneity.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) of human colon organoids (HCOs) from three healthy donors.
• EAEC 042 infection model to assess host-pathogen interactions.
• Analysis of cell type composition, gene expression, and cell-cell communication networks.

Main Results:

• Comparable EAEC adherence across donors, but distinct donor-specific cellular responses.
• Identification of seven distinct colonic epithelial cell clusters with unique baseline compositions.
• Three distinct host response phenotypes (hyperresponsive, intermediate, non-responsive) observed post-infection.
• Extensive donor-specific cell-cell communication networks identified.

Conclusions:

• Host epithelial responses to EAEC infection exhibit significant heterogeneity at the single-cell level.
• Intrinsic host factors play a critical role in determining EAEC disease outcomes.
• Human organoids provide a powerful platform for dissecting host heterogeneity in infectious diseases.