Dr. Saini and colleague at the Indian Institute of Technology, Bombay have used a mathematical model to track the gene expression pathway of a bacterium that causes whooping cough (or pertussis). The understanding of gene regulation along the growth and infection process for Bordetella could lead to new ways to block its action.
The Bordetella bacterium colonizes the respiratory tracts of several hosts, including humans, to cause the infection most commonly referred to as whooping cough. There are two stages of the infection, with the first being mild (cold like symptoms), followed by the intense coughing and difficulty breathing which creates the characteristic “whooping” sound for which the infection is named. This second stage of the infection is controlled by a specific set of genes in the bacterium DNA, and regulated by one pathway known as BvgAS.
This pathway BvgAS is a series of three phosphorylation reactions, where a phosphate group is added to specific proteins in turn, and the final protein then activates the genes responsible for virulence (infection). The addition or removal of a phosphate group is a standard way for cells to turn proteins “on” or “off” as needed. Figure 1 below shows the activation pathway of the final protein in the series (BvgA, triangle), which is the gene promoter.
The researchers were able to recover experimentally observed gene activation for four important classes of genes. They monitored where the pathway of interest changes from a repressed state (i.e. genes are inactive, or unexpressed), to an intermediate state, and finally to an active state (i.e. genes are expressed). The expression levels for each class of genes observed during the transitions are shown in Fig. 2 below.
Additionally, the same simulations were carried out on mutant bacteria containing one phosphorylation event in the pathway. This was done to understand the role of having three phosphorylation reactions for BvgAS, while typical pathways in bacteria have one or two events. This extra complexity was found to provide the bacterium with sensitivity and flexibility to respond to environmental factors, by changing the gene expression profile.
Understanding how the bacterium can respond to changing environmental factors by regulating gene expression could lead to new treatments for the infection in humans.
Read the full HOT paper by Mahendra Kumar Prajapa and Supreet Saini here: