A new research project by Michigan State University scientists will probe the mechanisms that drive disease and immunity at the cellular level, work which stands to revolutionize our understanding of why plants and animals, including humans, get sick.
The four-year project, made possible by a $1.2 million grant from the National Institutes of Health, will investigate a process by which pathogens can manipulate the organizational structure of a cell, thereby inhibiting its ability to respond to a threat.
Brad Day, professor in the MSU Department of Plant, Soil and Microbial Sciences, leads the project.
“We’re one of the first groups to really look into this area,” Day said. “The processes surrounding immunity and disease are a fundamental component of biology, and one our lab has been working for years to better understand.”
When a cell falls under attack by a pathogen, it triggers a response by the actin cytoskeleton – the tangled collection of microfilaments that gives the cell its shape – to activate genes that prohibit the invader from entering. Under normal conditions, the actin cytoskeleton resembles a spider web, each strand constantly moving. When under attack, however, that movement stops and the actin microfilaments bundle together.
Previous research from Day’s lab, which has been studying disease and immunity at the cellular level since 2006, revealed that pathogens are capable of inhibiting this process, keeping the actin from bundling and preventing the gene expression that would cause the cell to respond to the assault, leaving the organism vulnerable to infection.
This defensive feature of the cell is highly conserved, meaning it appears in a wide range of organisms, including humans. Past medical research has shown the actin cytoskeleton of many patients is not behaving as it should, leaving them open to disease. Discovering how the feature is breached could open up new approaches to the treatment of major human diseases, including Alzheimer’s, Parkinson’s and Huntington’s, as well as crop disease.
Tackling new scientific questions requires a cutting-edge approach and Day’s lab has developed the tools for the job. Using Arabidopsis, a small flowering plant commonly used as a model in plant biology due to its relatively simple genome, the team created a novel set of high-resolution imaging and analysis devices. These will allow them to identify specific changes in gene expression and actin cytoskeleton organization as the plant cell falls under attack by pathogens.
“We’re correlating specific changes in the actin cytoskeleton with the induction and expression of specific genes in the plant cell,” Day said. “If, say, a strand of actin is turned 90 degrees, we already have data that shows gene expression changes as a result, which can limit the plant’s ability to respond defensively. If a pathogen comes in and does that, the whole organism could be left open to attack. We want to find how exactly that’s happening.”
As Day’s team observes the interactions between pathogens and the actin cytoskeleton, they will employ another method developed with colleagues in Japan called “laser confocal microscopy” to quantify those changes. Through this technique, they will capture 100 images of the actin cytoskeleton every 10 seconds – 5,000 images per experiment – and run them through a computerized analysis program. The program breaks each image down and measures the behavior of each individual microfilament. This allows Day to see under what circumstances actin is kept from bundling to prevent infection.
“This project allows us to drill so far down into the nature of this mechanism that hopefully we uncover previously unobserved characteristics,” Day said. “This has major implications for human health. This has the potential to impact therapies and treatments for some of the most serious diseases we as humans face, and I’m so proud of my team for contributing to it.”