During infection, pathogens must adapt quickly to the conditions to thrive inside the body. A research team at the University of Basel, Switzerland, has uncovered how a key protein switches on the machinery that enables Leptospira 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 late 20th century, diseases that are transmitted from animals to humans, so-called zoonoses, have been on the rise. One of these is leptospirosis, an infectious disease that is becoming more common due to climate change. Leptospirosis causes around 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 regions with limited resources, and even in Switzerland, cases have occurred.
The disease is caused by pathogenic Leptospira bacteria. Patients get infected through contact with contaminated water or soil. If not treated early with antibiotics, the infection can lead to organ failure. When entering the human host, the bacterium switches on virulence factors, enabling it to survive and persist in the body. This process is controlled by the protein LvrB: when activated, it turns the bacterium from harmless to harmful.
Switch flips from inactive to active
Until now, it has been unclear how exactly this switch protein LvrB operates. In a recent “Nature Communications” study, Professor Sebastian Hiller’s team at the Biozentrum, University of Basel, has now elucidated 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 gets activated. More importantly, we have uncovered the general activation mechanism for this key class of proteins,” says Hiller. “Our findings will help scientists design drugs that keep LvrB turned off, preventing the pathogen from becoming virulent.”
Locked and Off
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 symmetric and inactive conformation, thus unable to activate virulence factors,” explains Elia Agustoni, the first author of the study. “This “off” position prevents the bacterium from producing virulence factors unnecessarily, for example when it is outside the body.”
Active and virulent
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 allow Leptospira 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 the 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 for leptospirosis, these mechanistic insights provide a blueprint for understanding a broad class of related signaling systems found across bacteria. Many of these belong to pathogens infecting humans, animals, and plants. “Our findings lay the foundation for uncovering a plethora of unexplored cellular processes, and will support the development of new antibiotics as well as agrochemicals,” emphasizes Hiller.
Nature Communications
Activation mechanism of the full-length histidine kinase LvrB from pathogenic Leptospira.