Hidden small RNA determines if cholera bacterium can infect humans

A small string of nucleic acids decides if the cholera bacterium can infect humans or live in the environment.

MEMPHIS, Tenn., May 14, 2026 /PRNewswire/ -- Scientists from St. Jude Children's Research Hospital have uncovered what gives Vibrio cholerae, the bacterium that causes cholera, the ability to colonize the human gut. Published today in Nature Communications, the researchers found that a small RNA embedded within another gene controls where cholera thrives, a discovery that could improve prediction and prevention strategies.

Infectious diseases remain the leading cause of pediatric mortality worldwide. V. cholerae causes a severe diarrheal disease leading to over 143,000 deaths and millions of cases each year, primarily affecting young children. While there are many strains of the V. cholerae species, only one can infect humans. The reason for this has been unclear for 50 years, hampering efforts to predict and prevent outbreaks.

"For decades, we've been trying to understand what allows cholera to infect humans," said corresponding author Salvador Almagro-Moreno, PhD, St. Jude Department of Host-Microbe Interactions. "The answer was right in front of us the whole time — this small RNA hiding inside another gene is the real culprit."

Researchers from the Almagro-Moreno lab previously compared bacterial DNA from patient and environmental samples, identifying variation in a gene called ompU. In this study, they discovered that the critical factor for infection was not the gene itself, but a small RNA encoded within it. Variations in this RNA had widespread effects on the expression of genes linked to human infection.

"We saw that this small RNA is the master regulator of host colonization and infection," Almagro-Moreno said. "Variants in the small RNA from clinical samples controlled about 85% of the genes related to human infection, compared to just 15% for environmental variants."

Small RNA variants have big consequences for colonization

One of the most important impacts of the small RNA's control was its effect on biofilm formation. Biofilm is a protective coating some bacteria produce, but it can trigger a strong immune reaction in mammals. In cholera strains with human-associated small RNA variants, biofilm formation was suppressed, enabling the bacteria to avoid critical immune barriers.

"Typically, these bacteria get stuck in the mucus layer lining our gut, allowing our immune system to arrive and eliminate them," Almagro-Moreno said. "Human-associated variants in the small RNA enable the bacteria to swim freely through this mucus layer, but when we mutated those small RNAs, the bacteria got caught and couldn't colonize the gut and cause infection."

To better understand which parts of the small RNA gave the cholera bacterium these adaptations to the mammalian gut, the researchers closely compared the sequences of this RNA between different strains of V. cholerae. Further analysis revealed that the small RNA has two distinct components: a variable region hidden within the ompU gene and a conserved region embedded outside it. This intrigued them and prompted the finding that the ompU gene itself can be freely exchanged between different bacteria.

Small RNA modularity provides flexibility

To understand how pathogens emerge in nature, the scientists mimicked the gene exchange process that innately happens in bacteria in their environment and swapped the variable regions of the small RNA. The swap reversed the bacterium's behavior, allowing strains encoding the environmental version of the small RNA to regain their former infection capabilities.

"We found that the variable region of the small RNA is modular, like interchangeable camera lenses," Almagro-Moreno said. "The conserved region is the part of the camera that always stays the same, but the bacteria can switch out their lenses, the gene containing the variable region, to adapt to different environments."

These findings provide new insight into how the cholera bacterium evolved to infect humans. Because this RNA is an essential component for human infection, it could help identify strains with outbreak potential.

Diarrhea is a catastrophic pediatric disease that remains one of the three leading causes of childhood mortality worldwide. "By identifying this small RNA, we've moved closer to predicting which strains cause cholera outbreaks and how they cause them," Almagro-Moreno said. "Our findings will help us improve prevention strategies to help children around the globe."

Authors and funding

The study's first author is Deepak Balasubramanian, St. Jude. The study's other authors are Qinqin Pu, St. Jude; and Cole Crist, University of Central Florida.

The study was supported by grants from the National Science Foundation (CAREER award 2045671), Burroughs Wellcome Fund Investigator in the Pathogenesis of Infectious Disease (1021977) and the American Lebanese Syrian Associated Charities (ALSAC), the fundraising and awareness organization of St. Jude.

St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is leading the way the world understands, treats, and cures childhood catastrophic diseases. From cancer to life-threatening blood disorders, neurological conditions, and infectious diseases, St. Jude is dedicated to advancing cures and means of prevention through groundbreaking research and compassionate care. Through global collaborations and innovative science, St. Jude is working to ensure that every child, everywhere, has the best chance at a healthy future.  To learn more, visit stjude.org, read St. Jude Progress, a digital magazine, and follow St. Jude on social media at @stjuderesearch.

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