UF Health researcher on team whose work could be vital in fighting drug-resistant bacteria

The battle that University of Florida Health researcher Eric Nelson, M.D., Ph.D., and his international team of collaborators are unraveling began several billion years ago when bacteria and their viral killers began a veritable genetic arms race.

This seemingly eternal struggle for supremacy continues today, with implications for diseases killing tens of thousands of people around the world each year.

“It’s a predator-prey relationship that is critically important to understand,” Nelson said.

Nelson and collaborators published a study in Science on April 18 revealing key insights into how bacteria killers called bacteriophages or phages impact the severity of the waterborne diarrheal disease cholera. Cholera kills between 21,000 and 143,000 people annually worldwide. It is a disease of poverty, striking regions lacking clean drinking water and sanitation.

The team conducted what it believes to be one of the largest genetic studies to analyze the dynamic relationship between cholera bacteria, their bacteriophages and antibiotics.

The study underscores the possibility of creating new strategies to use bacteriophages to kill drug-resistant bacteria in cholera and other diseases that have plagued civilization for centuries, said Nelson, the study’s senior author.

“What we’ve discovered will be a pathway to new diagnostics, a pathway to better think about antibiotic resistance mitigation,” said Nelson, an associate professor in the UF College of Medicine’s department of pediatrics and the UF College of Public Health and Health Professions’ department of environmental and global health. “The hope is that we will reveal a truth we’ve been blinded to for a century.”

A key finding involves a concept called “effective predation.” The researchers found a higher ratio of phage predators to their bacterial prey was associated with milder cholera cases. The team said it is the first to show the genetic underpinnings of this ratio.

“The phages are putting the evolutionary squeeze on the bacterial pathogen,” said Nelson, a member of UF Emerging Pathogens Institute.

This ratio can be used as a marker of disease severity, informing a physician’s decisions on treatment. It might also predict disease progression.

The researchers used advanced genomic techniques to analyze the interaction of bacteria and the bacteriophages in 2,574 stool samples from cholera patients in Bangladesh, a nation with one of the world’s highest cholera rates — about 100,000 cases yearly. Samples were collected in 2018 and 2019.

Nelson said a crucial collaborator on the project is Ashraful Islam Khan, M.D., of the International Centre for Diarrhoeal Disease Research, Bangladesh, or icddr,b. Khan headed the monumental effort to collect samples and patient information across the Asian nation.

Another key contributor is Jesse Shapiro, Ph.D., an associate professor at McGill University in Montreal. He conducted a genetic analysis of samples with the study’s lead author, Naïma Madi, Ph.D., a postdoctoral researcher at McGill.

Documenting the genetic arms race between the bacterium and its phages complicates the study of cholera and phage ecology. Each evolves to thwart the other’s defenses. One adapts, the other responds. If the phages have the upper hand, the genetic diversity of the bacteria increases. Then, the population of phages falls. The virus responds with genetic adaptations, eventually thriving again.

That microscopic battle in which both sides retool their genetics is analogous to warfare.

“In warfare, someone has a handgun, the other side gets a handgun,” Nelson said. “They get a shotgun, someone else gets a shotgun. One gets a bazooka, and the other side gets a bazooka. And as this arms race happens, the front line is still in the same spot because the pressures are equal over time.”

Nelson said more studies, including a clinical trial, are needed before effective phage therapies are developed. The study, among several other sources, received support from the National Institutes of Health and the Canadian Institutes for Health Research Project.