Positive feedback and temperature mediated molecular switch controls differential gene regulation in Bordetella pertussis

TL;DR

This study presents a mathematical model of the BvgAS two-component system in Bordetella pertussis, revealing a temperature-induced molecular switch that influences gene regulation and toxin expression.

Contribution

It introduces a novel mechanism of transcriptional interference and provides a quantitative framework for understanding temperature effects on gene regulation in B. pertussis.

Findings

Temperature induces a sharp molecular switch in BvgAS system.

Model captures differential gene regulation and toxin gene expression.

Mutant analysis shows impaired phosphorylation affects system behavior.

Abstract

Based on the phosphorelay kinetics operative within BvgAS two component system we propose a mathematical framework for signal transduction and gene regulation of phenotypic phases in Bordetella pertussis. The proposed model identifies a novel mechanism of transcriptional interference between two promoters present in the bvg locus. To understand the system behavior under elevated temperature, the developed model has been studied in two different ways. First, a quasi-steady state analysis has been carried out for the two component system, comprising of sensor BvgS and response regulator BvgA. The quasi-steady state analysis reveals temperature induced sharp molecular switch, leading to amplification in the output of BvgA. Accumulation of a large pool of BvgA thus results into differential regulation of the downstream genes, including the gene encoding toxin. Numerical integration of the full network kinetics is then carried out to explore time dependent behavior of different system components, that qualitatively capture the essential features of experimental results performed in vivo. Furthermore, the developed model has been utilized to study mutants that are impaired in their ability to phosphorylate the transcription factor, BvgA, of the signaling network.