Published on: January 10, 2017

Article Source: University of Delaware

Abstract: Phage therapy, the one which exploits the ability of certain viruses to infect and replicate within bacteria has shown remarkable evidence in treating antibiotic-resistant bacterial infections. However, designing such therapies depends on understanding how phages work. Phages can either kill the cell immediately, or become dormant and kill it later, with a high level of precision in kill time.

Full Article:

Phage therapy, the one which exploits the ability of certain viruses to infect and replicate within bacteria has shown remarkable result in treating antibiotic-resistant bacterial infections. However, designing such therapies depends on understanding how phages work. Phages can either kill the cell immediately, or become dormant and kill it later, with a high level of precision in kill time.

phage-resized

However, designing such therapies requires solid understanding of how phages do their work.

“Phages can kill the cell immediately, or they can become dormant and kill it later,” saidAbhyudai Singh, assistant professor of electrical engineering, University of Delaware.”The data revealed a high level of precision in the kill time,” he added. “It takes about one hour for the virus to complete the process, but questions remain about how the cells control this precision in timing.”

The research has been done in collaboration with Singh and John Dennehy from Queens College and the Graduate Center of the City University of New York and the findings have been released in a paper, “A First-Passage Time Approach to Controlling Noise in the Timing of Intracellular Events,” and published online in the Proceedings of the National Academy of Sciences on Jan. 9.

According to AbhyudaiSingh,”the problem is that while there is an overall precision to this process, there is also inherent randomness from cell to cell. So our mathematical model is basically a framework, or model system, that brings order to this randomness and provides general biological insights that can be applied in the laboratory.”

Singh further explained that the holins, the proteins essential for lysing, or destroying, the cell first accumulate on the cell membrane, reach a critical threshold, and then form holes that rupture the cell and release phage “babies.” But the same gene that expresses holin also expresses another protein called antiholin.

“It’s curious that nature would make two versions of a protein that cancel each other out,” he added. “But it turns out that it’s actually antiholin which makes the timing precise. If we remove antiholin, the variation in the process increases.”

According to the researcher, the formulas developed in the work shed counterintuitive insights into the regulatory mechanisms needed for scheduling an event at a precise time with minimal fluctuations.

“While we expected feedback to be an important part of the triggering mechanism, it turns out that negative feedback regulation can actually amplify noise, or confusion, in event timing,” he says. “So in some cases, such as with our work on lysis in bacteriophages, precision in timing is obtained with no feedback at all.”

“We believe that the analytical results and insights we obtained in this work have broader implications for timing phenomenon in chemical kinetics, ecological modeling and statistical physics.”

Journal Reference:

Khem Raj Ghusinga, John J. Dennehy, Abhyudai Singh. First-passage time approach to controlling noise in the timing of intracellular eventsProceedings of the National Academy of Sciences, 2017; 201609012 DOI: 10.1073/pnas.1609012114