During infection, pathogens must quickly adapt to the conditions in order to thrive inside the body. A research team at the University of Basel, Switzerland, has revealed how a key protein activates the enabling mechanism Meticulous pathogens to survive and cause disease. The findings provide new insights into how pathogens regulate their virulence and may open new avenues for therapeutic interventions.
Since the end of the 20th century, diseases transmitted from animals to humans, so-called zoonoses, have increased. One of them is leptospirosis, an infectious disease that is becoming more common due to climate change. Leptospirosis causes about one million severe cases worldwide each year, and an estimated 60,000 people die from it. The disease is a serious public health problem in areas with limited resources, and outbreaks have even occurred in Switzerland.
Disease is caused by pathogens Meticulous bacteria. Patients become infected through contact with contaminated water or soil. If not treated promptly with antibiotics, the infection can lead to organ failure. When it enters the human host, the bacterium activates virulence factors, allowing it to survive and persist in the body. This process is controlled by the LvrB protein: when activated, it turns the bacterium from harmless to harmful.
Toggle rollovers from inactive to active
Until now, it was not clear exactly how this switch protein LvrB works. In a recent “Nature Communications” study, Professor Sebastian Hiller’s team at the Biozentrum, University of Basel, has now clarified the protein’s three-dimensional structure and mode of action.
We now understand at the atomic level how the molecular switch works and how it is activated. Most importantly, we have revealed the general mechanism of activation of this key class of proteins. Our findings will help scientists design drugs that keep LvrB turned off, preventing the pathogen from becoming virulent.”
Professor Sebastian Hiller, University of Basel
Locked and disabled
LvrB is part of a communication system that regulates the activity of hundreds of genes linked to bacterial virulence – in other words, the pathogen’s ability to cause disease. “In the off state, LvrB is locked in a symmetrical and inactive conformation, making it unable to activate virulence factors,” explains Elia Agustoni, first author of the study. “This ‘off’ position prevents the bacterium from unnecessarily producing virulence factors, for example when outside the body.”
Active and infectious
Host signals activate a signaling cascade that leads to chemical modifications of LvrB, resulting in structural rearrangements. “Conformational changes in LvrB disrupt its symmetry, thereby activating the protein,” says Agustoni. In its “on” state, LvrB can transfer the signal to its partner protein, which has also been identified by the researchers. Together, they activate virulence genes that enable Meticulous to spread in the body.
Implications for other infectious diseases
The researchers suggest that interfering with the structural changes in LvrB that keep it in an inactive state could be a promising strategy to weaken the virulence of pathogens and thus prevent infections. This approach could also reduce the risk of antibiotic resistance.
Beyond its relevance to leptospirosis, these mechanistic insights provide a blueprint for understanding a broad class of related signaling systems found in bacteria. Many of them belong to pathogens that infect humans, animals and plants. “Our findings lay the foundation for uncovering a wealth of unexplored cellular processes and will support the development of new antibiotics as well as agrochemicals,” Hiller emphasizes.
