ToxR protein’s binding to DNA reveals insights into cholera pathogenesis

Dr. Miquel Coll, along with his team at the Institute for Research in Biomedicine (IRB Barcelona) and the Institute of Molecular Biology of Barcelona (IBMB-CSIC), in collaboration with researchers led by Dr. Eric Krukonis at the University of Detroit Mercy in the U.S., has made a significant breakthrough in understanding the molecular mechanism that triggers cholera, a disease caused by the bacterium Vibrio cholerae.

In their study, published in the journal PNAS, the scientists employed X-ray diffraction techniques using synchrotron radiation and artificial intelligence to reveal the atomic structure of the ToxR protein when bound to the DNA of two promoters responsible for the virulence genes in Vibrio cholerae.

ToxR is a transcription factor protein that plays a crucial role in activating the toxT and ompU genes, which are responsible for the production of the cholera toxin. This toxin leads to severe diarrhea and dehydration, which can be fatal if not treated promptly.

The study found that ToxR binds to multiple regulatory sequences in bacterial DNA, either in tandem or inverted, thereby recruiting RNA polymerase, which is responsible for gene transcription.

Dr. Albert Canals, the first author of the research, explains that ToxR acts as a transmembrane transcription factor that detects bile salts when the bacterium reaches the human intestine. Upon detection, a signal is transmitted to the DNA inside the bacterium, initiating the toxicity cascade that triggers the disease.

Dr. Eric Krukonis, another researcher involved in the study, notes that ToxR has been extensively studied but its precise interaction with DNA has remained elusive. This research demonstrates that ToxR recognizes the structure of DNA rather than specific DNA sequences, offering insights into its role in activating virulence genes and removing repressor proteins that prevent the expression of factors like cholera toxin until the bacterium enters the host.

This groundbreaking study enhances our understanding of the molecular mechanisms behind cholera, providing valuable insights that could pave the way for the development of new treatments for this deadly disease.

The forgotten pandemic

Cholera is a diarrheal illness caused by consuming contaminated food or water contaminated with the bacterium Vibrio cholerae. While many developed countries have successfully eradicated cholera, it remains a significant public health threat in countries with inadequate sanitation and reflects social inequality and lack of development.

According to the World Health Organization (WHO), cholera originated in the Ganges delta in India and spread worldwide during the 19th century. It has caused six major pandemics, resulting in the deaths of millions of people across all continents. Currently, we are facing the seventh pandemic of this infectious disease, which is endemic in many developing countries and predominantly affects children.

In 2022, 29 countries reported cases of cholera, including Haiti, Malawi, Yemen, and Syria, where large-scale epidemic outbreaks occurred. The global incidence of cholera has been increasing in recent years, with cases becoming more frequent, widespread, and severe. Climate change plays a significant role in this trend, as it leads to floods, droughts, and population displacement. Armed conflicts and natural disasters further exacerbate the situation by limiting access to safe drinking water and facilitating the spread of the disease. The resurgence of cholera in 2023 has raised concerns among international organizations such as UNICEF and WHO.

Source: Institute for Research in Biomedicine (IRB Barcelona)

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