Temporal tuning of switch-like virulence expression resolves environmental uncertainty through phenotypic...

Area of Science:

• Microbiology
• Bacterial Pathogenesis
• Gene Regulation

Background:

• Gene regulatory networks adapt to environmental uncertainty, with stimuli rarely being precise.
• Intracellular bacterial pathogens face dynamic, hostile host environments, shaping virulence gene regulation.
• Salmonella Pathogenicity Island 2 (SPI-2) is crucial for Salmonella Typhimurium's intracellular replication.

Purpose of the Study:

• To investigate if Salmonella Typhimurium (STm) tunes SPI-2 transcriptional responses to intracellular-like environments.
• To evaluate the capacity for probabilistic gene expression in response to environmental cues.

Main Methods:

• Utilized live-cell reporters and single-molecule fluorescence in situ hybridization (smFISH).
• Conducted experiments in in vitro inducing environments mimicking intracellular conditions.
• Analyzed single-cell transition dynamics, growth rates, and lineage.

Main Results:

• Identified bimodal expression of SPI-2 in clonal populations, with cells progressively transitioning to an expressing state.
• Demonstrated that transition timing varies across generations and is modulated by signal strength and growth rate.
• Linked SPI-2 heterogeneity to SsrA signaling and SsrB concentration, revealing switch-like activation dynamics.

Conclusions:

• STm probabilistically tunes the fraction of SPI-2 expressing cells based on perceived intracellular environment likelihood.
• This strategy resolves uncertainty in ambiguous environments, enhancing bacterial survival and virulence.
• Single-cell responses are linked to cell growth and lineage, providing insights into adaptive mechanisms.