The secret lives of bacteria: How they evade viral attack
UTSW study uncovers hundreds of ‘phage defense’ genes, could lead to new methods to fight infection
DALLAS – Aug. 11, 2025 – Researchers at UT Southwestern Medical Center have identified more than 200 strategies used by bacteria to avoid viral infection. Their findings, published in Cell Host & Microbe, shed light on a microbial “arms race” that could lead to new approaches to fight infectious bacteria.
“There’s a wealth of phage defense strategies in nature that we don’t have a handle on,” said Kevin Forsberg, Ph.D., Assistant Professor of Microbiology at UT Southwestern. “These findings could one day help improve therapies for treating antibiotic-resistant bacterial infections.”
Dr. Forsberg co-led the study – the first independent publication of the Forsberg Lab – with Luis Rodriguez-Rodriguez, a fifth-year UTSW graduate student.
Like all living things, bacteria are under constant risk of infection by viruses. Those that infect bacteria are collectively known as bacteriophages, or “phages.” Consequently, bacteria have evolved various ways to fight this threat, while viruses have developed strategies to evade bacterial defenses – the majority of which remain uncharacterized, Dr. Forsberg explained.
Most research to identify antiphage defenses has relied on the propensity of defense-related genes to cluster in the bacterial genome; thus, identifying one defense gene often leads to others, simply based on its location within each bacterium’s single, circular chromosome. Although this “guilt by association” strategy has identified many antiphage genes, scientists have hypothesized that hundreds more exist.
Taking a new tack, Dr. Forsberg, Mr. Rodriguez-Rodriguez, and their colleagues used DNA extracted from bacteria living in human fecal and oral samples, as well as grassland soil samples. After breaking up this DNA into small pieces, each holding about three or four genes, the researchers inserted individual pieces into Escherichia coli, bacteria that’s found in human intestines and often used as a lab model. They then grew these bacteria in petri dishes coated with one of seven types of phages that attack E. coli, looking for microbes that survived phage attack and grew into colonies – an indication that the inserted snippet of DNA held a phage-fighting gene.
This strategy turned up over 200 phage defense systems, including many previously unknown. A closer look showed that several of these genes encoded nucleases, or enzymes that cleave the nucleic acids DNA or RNA. Several more encoded DNA modification-dependent enzymes, generating enzymes that only cleave nucleic acids onto which sugars, proteins, or other molecules are bound – a common strategy some viruses use to avoid bacterial restriction enzymes, another form of phage defense.
Other phage defense genes encoded proteins present on the surfaces of some bacterial species that prevent phages from binding. The researchers also found some genes that appear to cause “abortive infection,” in which bacteria become dormant or die after they are infected to protect nearby bacteria from infection.
However, Dr. Forsberg said, the majority of phage defense genes that turned up in the study have unknown functions. He and his colleagues plan to investigate their roles in future research.
Other UTSW researchers who contributed to this study are Vincent Tagliabracci, Ph.D., Associate Professor of Molecular Biology; and James Pfister, B.S., Arabella Martin, B.S., and Luis Mercado-Santiago, B.S., graduate student researchers.
Dr. Forsberg is a W. W. Caruth, Jr. Scholar in Biomedical Research.
This study received funding from the National Institutes of Health (DP2-AI154402); The Welch Foundation (I-1911); the Howard Hughes Medical Institute (HHMI) Emerging Pathogens Initiative; the Searle Scholars Award program; the Endowed Scholars Program at UT Southwestern; and the HHMI Gilliam Fellows Program.
About UT Southwestern Medical Center
UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 24 members of the National Academy of Sciences, 23 members of the National Academy of Medicine, and 13 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 140,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5.1 million outpatient visits a year.