Until now, it was not clear how Vibrio cholerae , the bacteria that causes cholera, managed to penetrate the defenses of the intestine to colonize it and cause the infection, which in severe cases is characterized by acute diarrhea and dehydration, and causes nearly 150,000 deaths annually. But a group of researchers from the Leloir Institute Foundation (FIL) discovered the way in which a protein in the microorganism regulates its production of toxins, allowing it to go unnoticed and only express them when it is in a safer area for its survival. A finding that could lead to therapies that seek to take advantage of this mechanism and, thus, avoid the disease.
“During any infection, a battle is fought between the bacteria that tries to colonize us and our body, which fights to fight it. The defense mechanisms of the human body and the strategies of pathogens to overcome them are many, but in recent years one that involves the so-called reactive sulfur species (RSS) has emerged as particularly relevant: these are some sulfur compounds that, although essential for any organism, are toxic in high concentrations,” biologist Giuliano Antelo , one of the authors of the article published in the Journal of Biological Chemistry (JBC) and a doctoral fellow in the FIL Physical Chemistry of Infectious Diseases Laboratory, directed by the doctor in Chemical Sciences Daiana Capdevila.
In the early stages of infection, when the pathogen has just entered the digestive tract, an inflammatory response is generated; In particular, the bacteria in the intestine themselves begin to release an excess of these sulfur compounds. “This would be lethal for the microorganism if it did not have ways to deal with it,” Antelo highlighted. And he added: "In this work we discovered that the HlyU protein of Vibrio cholerae specifically detects RSS and thus prevents, we believe, the synthesis of toxins until the bacteria leaves the area with a high presence of these species and lodges in the wall, where "It has more oxygen and chances of survival."
The doctor in Organic Chemistry Cristian Pis Diez , postdoctoral fellow and first author of the article, offered more details about the intricate biochemical process: “The reaction of HlyU against RSS will be given, among other things, by the medium in which it is found. the bacteria: if it is rich in sulfur species, as happens in the lumen of the small intestine, the production of the toxin is attenuated, allowing it to survive and progress with the infection. “Once the pathogen reaches the surface of the intestine, however, the lower presence of sulfur leads to greater production of the toxin.”
This ability to regulate the activation of the protein gives it an adaptive advantage, since it prevents a toxin from being expressed at the wrong time of colonization, when it would awaken the body’s natural defenses, added Pis Diez.
In the last five years, the FIL Physical Chemistry of Infectious Diseases Laboratory group determined that bacteria have sensors for sulfur compounds, the same ones that give the egg its rotten smell. “Today we know that these compounds are very important in different biological processes. In this new work we demonstrate how they affect the ability of Vibrio cholerae to regulate its toxins until it settles permanently in the part of the intestine where it is not so threatened,” Capdevila described.
A preventable disease
Cholera is contracted by ingesting water or food contaminated with the bacteria. It has a short incubation period (ranging from 12 hours to five days) and while most people are asymptomatic or have mild or moderate symptoms, around 20% can develop acute diarrhea with severe dehydration and be at risk of death. Although it can be easily treated with a rehydration solution, cholera remains a global threat due to its impact on populations that lack access to adequate healthcare.
According to the World Health Organization (WHO), since mid-2021 the world is facing “a sharp rebound in the seventh cholera pandemic, characterized by the number, magnitude and concurrence of multiple outbreaks, the spread to areas that “They had been free of cholera for decades and had alarmingly high mortality rates.”
“In the study we focused on Vibrio cholerae since it is the cause of a prevalent and often lethal disease in humans, but it is not the only organism to use the mechanism to detect sulfur compounds. In fact, this work was based on previous research from our laboratory on other similar proteins. In particular, about that of a non-pathogenic bacteria called Rhodobacter capsulatus,” said Antelo, author of another work recently published in PNAS Nexus in a collaboration of Japanese and American researchers. And he added: “I think it is a good example of why science should not only study topics whose importance is obvious. Many times, systems that are not so well known or relevant in terms of human health are triggers to better understand those that are.”
At a time when antibiotics as a traditional treatment method against bacteria are no longer working, scientists emphasize the need to explore alternatives that can be developed in the short or medium term to replace them or, in the best of cases, , complement them.
“Understanding the mechanisms by which a bacteria invades different parts of our body, in this case the intestine, opens up a broader picture for us regarding what strategy to adopt to confront it,” said Pis Diez. And he concluded: “We can, for example, develop or reposition drugs that inhibit the regulatory mechanisms of toxin production, which are what allow this colonization. This would leave the bacteria more defenseless within our body, which would allow it to be treated more effectively by an antibiotic, or even be defeated by our immune system.”
