Researchers at the ADA Forsyth Institute have uncovered a previously unknown mechanism that shapes interactions between Saccharibacteria and their bacterial hosts, providing new insight – and an entirely new avenue for investigation – into one of the most enigmatic groups of microbes in the human microbiome.
The discovery, reported in the Proceedings of the National Academy of Sciences (PNAS), reveals for the first time that a prophage encoded by the bacterial host Schaalia odontolytica can infect its Saccharibacterial episymbiont TM7x and alter the dynamics of their symbiotic relationship.
Saccharibacteria belong to the Candidate Phyla Radiation (CPR), a large group of ultra-small bacteria with highly reduced genomes. Unlike most bacteria, Saccharibacteria depend on other microbes for survival and live attached to the surface of host cells. The first cultivated human-associated Saccharibacterium, TM7x, was isolated and characterized in 2015 by ADA Forsyth Professor Xuesong He and colleagues, providing a unique model for studying these unusual organisms.
Although Saccharibacteria are widespread in the human oral microbiome and have been linked to health and disease, including periodontal disease, many aspects of their biology remain poorly understood. The new study reveals an unexpected viral component within this relationship.
“We discovered that a prophage carried by the host bacterium can be activated and subsequently infect its Saccharibacterial partner,” said Dr. Ajay Kumar, lead author of the study. “This finding demonstrates that CPR bacteria participate in viral infection networks, opening an entirely new area of investigation into Saccharibacteria biology and ecology.”
Bacteriophages, or phages, are viruses that infect bacteria. Some phages exist as dormant genetic elements known as prophages, which remain integrated within bacterial genomes until activated by specific environmental or physiological signals.
The ADA Forsyth team identified a prophage, named Xhp1, embedded in the genome of S. odontolytica. When activated, Xhp1 is released from the host bacterium and infects TM7x. The researchers found that this infection influences the delicate balance between the host and its episymbiotic partner, revealing a previously unrecognized regulatory mechanism within this interspecies relationship.
“This discovery adds a completely new dimension to our understanding of episymbiosis,” said Dr. He, senior author of the study. “When TM7x attaches to its host, it triggers profound physiological changes in the host cell. We now show that these interactions can also lead to activation of a prophage that targets the Saccharibacterium itself. This introduces another level of complexity to a symbiotic relationship that has fascinated us for years.”
The findings provide the first direct evidence that CPR bacteria are integrated into phage-host interaction networks. More broadly, the study highlights how viruses may influence the evolution, stability, and ecological function of microbial partnerships within complex communities such as the oral microbiome.
For Dr. Pu-Ting Dong, co-corresponding author and former ADA Forsyth Postdoctoral Fellow who recently established her laboratory at Stony Brook University, the findings underscore the value of exploring unconventional microbial systems. “Saccharibacteria continue to surprise us,” said Dr. Dong. “Discovering that a host-encoded prophage can directly infect and regulate an episymbiotic bacterium demonstrates that these interactions are far more intricate than previously appreciated. We hope this work inspires further studies into the role of phages in shaping microbial ecology and evolution.”
The work also raises intriguing evolutionary questions about how hosts, episymbionts, and phages have co-evolved. Rather than being a simple interaction between two organisms, the researchers suggest that these relationships may involve multiple layers of biological regulation and adaptation.
“When you think about it from an evolutionary perspective, these relationships are unlikely to be as simple as one organism benefiting while the other suffers,” Dr. He said. “Our goal is to understand the microbial ecosystem as a whole. By uncovering how each component contributes to the community, we can gain a more complete understanding of how Saccharibacteria influence human health and disease.”
The study, titled “A host-encoded prophage targets a Candidate Phyla Radiation bacterium and shapes episymbiotic interactions,” establishes a new framework for investigating viral influences on CPR bacteria and opens the door to future studies exploring the role of phages in shaping microbial symbioses throughout the human microbiome.
