Pathogen Cell-to-Cell Variability Drives Heterogeneity in Host Immune Responses

Area of Science:

• Immunology
• Microbiology
• Genomics

Background:

• Immune cell and bacterial interactions dictate infection progression.
• Population-level studies mask crucial cell-to-cell variation in host responses.
• Understanding this variation is key to deciphering infection dynamics.

Purpose of the Study:

• To investigate gene expression variation underlying distinct infection outcomes.
• To monitor infection phenotypes at the single-cell level.
• To link bacterial heterogeneity to host immune response variability.

Main Methods:

• Developed an experimental system combining single-cell RNA sequencing (scRNA-seq) with fluorescent markers.
• Probed individual macrophage responses to invading Salmonella.
• Analyzed gene expression and bacterial factor activity at the single-cell level.

Main Results:

• Host cell response variation is driven by heterogeneous bacterial factor activity.
• Variable PhoPQ activity in Salmonella modifies lipopolysaccharide (LPS).
• This bacterial modification leads to diverse host type I interferon responses.

Conclusions:

• Demonstrated a causative link between host and bacterial variability.
• Cell-to-cell variation in bacteria can drive significantly different host immune responses.
• Co-variation has critical implications for in vivo host-pathogen dynamics.