Intracellular mechanisms shown to promote spread of deadly bacterial infection

Northwestern Medicine investigators have discovered novel protein mechanisms that promote the rapid spread of Vibrio vulnificus, a rare but lethal bacteria that can cause vibriosis and sepsis, according to findings published in the Proceedings of the National Academy of Sciences.

Vibrio vulnificus bacteria live in warm coastal waters and can cause severe infection when ingested. Most people contract vibriosis from the bacteria by eating raw or undercooked shellfish, particularly oysters, or by swimming with an exposed wound.

About 150 to 200 people in the United States get vibriosis each year. However, 20% of them will succumb to the disease, according to the Centers for Disease Control and Prevention. The number of cases continues to increase due to climate change, and people who are immunosuppressed, particularly those with liver disease, are at higher risk of disease.

“It’s really the primary reason why you hear that you’re not supposed to consume oysters in months that don’t have an ‘r’ in them; because the warming waters of the ocean allow Vibrio vulnificus to grow and can cause this deadly disease,” said Karla Satchell, Ph.D., the Anne Stewart Youmans Professor of Microbiology and senior author of the study.

For more than a decade, Satchell’s laboratory has been studying vibriosis and the underlying mechanisms that enable Vibrio vulnificus to damage the intestinal wall and secrete toxins that cause severe gastrointestinal infection.

Previous work from Satchell’s group discovered this infection is mediated by the production of a large toxin called the Multifunctional-Autoprocessing Repeats-In-Toxin (MARTX). Within MARTX are even smaller toxins that promote infection, the most prevalent being the Makes Caterpillars Floppy-like (MCF) toxin.

Furthermore, Satchell’s group had discovered that the MCF toxin interacts with a particular protein subtype called adenosine diphosphate ribosylation factors (ARFs) that help mediate cellular function and are present in all eukaryotic cells.

“We think maybe what’s allowing Vibrio vulnificus to cause these various infections is these conserved proteins that it’s using for its activation,” said Alfa Herrera, Ph.D., senior research associate in the Satchell laboratory and lead author of the study.

In the current study, the scientists used a machine learning technique, called Alphafold2, to predict the structure of these human proteins interacting with the MCF toxin that promotes Vibrio vulnificus infections. Using this technique, the scientists found that MCF attaches to and degrades half of all Rab family guanosine triphosphatases (GTPases), proteins that support all aspects of cellular function and survival.

“It was really exciting because it allowed us to determine how it was targeting these proteins, how it was actually causing their degradation that led to cell death,” Herrera said.

This mechanism driven by MCF to promote infection has also been observed in other bacteria, according to Herrera, suggesting that this mechanism could be a promising therapeutic target for treating other diseases with dysregulated Rab GTPases, including cancer.

“We’re thinking beyond infections, that if we can maybe manipulate our particular toxin to target the particular proteins that we want, then maybe we can use this to mediate human disease,” Herrera said.

The study also highlights the direct impact climate change has on the spread of disease, particularly in the U.S., and how studying the disease and monitoring its prevalence can inform preventive public health measures, Satchell said.

“There’s a lot of really cool research going on looking at how climate change impacts infections in the United States and Vibrio vulnificus is one of the core models that’s being used to track that because it is a rare disease that is increasing in incidence with warming seawaters,” Satchell said.