Microbiologists and plant scientists say they’ve pinpointed a genetic weakness in cholera’s armor, which could lead to future treatments.
The current cholera pandemic began in Indonesia in 1961. Rather than fade away like its six previous worldwide outbreak predecessors, the strain is thriving and actually picking up steam.
Now, a new discovery shows the key genetic change the seventh pandemic acquired to thrive for more than 50 years.
The research reveals the first ever signaling network for a new bacterial signal, cyclic GMP-AMP (cGAMP), in the human cholera pathogen. Researchers also identified the first protein receptor of cGAMP as a phospholipase enzyme that remodels the V. cholerae membrane when cGAMP is produced.
“When this pandemic emerged, it virtually displaced all of the other V. cholerae isolates, or previous strains, on a worldwide scale,” says Chris Waters, microbiology professor at Michigan State University, who co-led the study with Wai-Leung Ng, a microbiologist at Tufts University.
“No one really knows why this happened. Our discovery of cGAMP synthase and phospholipase, which are present only in the seventh pandemic, could be key drivers of the seventh cholera pandemic.”
As reported in the Proceedings of the National Academy of Sciences, the evolution of the new signaling ability has contributed to the current strain—nicknamed “El Tor”—in causing around 95,000 deaths annually.
Just last year in Yemen, more than 1 million people contracted cholera and nearly 2,200 people died, making it one of the largest cholera outbreaks in world history.
Serendipity and interdisciplinary research contributed to the discovery, the researchers say. Even though they were postdoctoral fellows at Princeton University together, Waters and Ng didn’t realize they were studying the same genetic pathway until they landed their positions at their respected universities. Once they began to compare notes, they realized their research had real potential to understand this new cholera pandemic.
Graduate students Geoff Severin in the Waters lab and Miriam Ramliden in the Ng lab led the team to the Vibrio seventh pandemic island to find the genetic advances that allowed El Tor to find the traits none of its predecessors possessed. On this atoll of around 20 newly acquired genes was where they found the buried treasure of the phospholipase cGAMP receptor.
Waters knew that Christoph Benning, a renowned plant scientist and director of the Michigan State-DOE Plant Research Laboratory, was an expert in lipids and would possibly have some leads on the phospholipase—enzymes that degrade membrane building blocks—on which they were focusing.
“I immediately answered that yes we would like to help and that we could contribute to this research,” Benning says. “If you break it down to the biochemistry, it doesn’t matter if it’s a human, bacterium, or plant; we have many of the same genes and enzymes.”
Benning enlisted the help of Kenny (Kun) Wang, a former graduate student in his lab who had become an expert on these types of plant proteins, which are tricky to produce as they can destroy cells in the process.
He obtained and made the cholera phospholipase work in a test tube so the team could study how it is controlled by cGAMP.
Now that the scientists have unearthed the treasure, they’re looking for the keys to unlock one of El Tor’s greatest strengths, and turn it against itself.
“We think this new system is one of the key elements that led to the emergence and persistence of the current pandemic,” Ng says. “Our future research will try to understand the role that the cGAMP/phospholipase system played in this emergence.”
The National Institutes of Health, the National Science Foundation, and the Department of Energy funded the work.
Source: Michigan State University