Discovery of molecular switch reveals how Leptospira activates virulence phase

Structural study from the University of Basel has shown how the LvrB protein controls virulence in Leptospira offering a route to tackle infection without antibiotics

A research team at the University of Basel, Switzerland, has clarified how a key protein enables Leptospira bacteria to adapt rapidly within the human host and initiate disease. The study has provided a detailed account of how the protein LvrB acts as a molecular switch with control over virulence and so offers a mechanistic framework that could inform alternative therapeutic strategies to antibiotics.

Zoonotic infections – diseases that transmit from animals to humans – have increased since the late twentieth century, with environmental change and globalisation cited as major drivers. Leptospirosis has emerged as a persistent and in some regions expanding public health concern. The disease, caused by pathogenic Leptospiraspecies, has accounted for around one million severe infections each year worldwide, with approximately 60,000 deaths. Transmission typically occurs through exposure to contaminated water or soil, often in settings with inadequate sanitation infrastructure. If clinicians do not initiate antibiotic therapy at an early stage, infection can progress to multi-organ failure.

Successful infection depends on the pathogen’s capacity to sense host conditions and activate virulence programmes at the appropriate moment. In Leptospira, this transition from an environmentally adapted organism to a host-adapted pathogen depends on the protein LvrB. When inactive, the bacterium remains in a relatively benign state. However, upon activation LvrB initiates a cascade that enables survival, persistence and dissemination of the bacterium within the host.

Until recently, the molecular basis of this transition has remained poorly defined. In the study Professor Sebastian Hiller and colleagues at the university’s Biozentrum – which is its central life sciences institute – have determined the three-dimensional structure of LvrB and have characterised its activation mechanism at atomic resolution. The work has combined structural biology with biochemical analysis to resolve how conformational changes in the protein translate into functional output.

“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,” said Hiller.

“Our findings will help scientists design drugs that keep LvrB turned off, preventing the pathogen from becoming virulent,” he said.

LvrB forms part of a broader signalling network that regulates the expression of hundreds of genes associated with pathogenicity. In its inactive state, the protein adopts a symmetric conformation that prevents interaction with downstream partners. This structural arrangement effectively suppresses virulence factor production when the bacterium resides outside a host, where such activity would impose unnecessary metabolic cost.

“In the off state, LvrB is locked in a symmetric and inactive conformation, thus unable to activate virulence factors,” said Dr. Elia Agustoni.

“This off position prevents the bacterium from producing virulence factors unnecessarily, for example when it is outside the body,” he said.

Host-derived signals initiate a signalling cascade that modifies LvrB chemically which in turn induces structural rearrangements. These conformational changes disrupt the symmetry of the protein and enable it to adopt an active state. In this configuration, LvrB interacts with a partner protein identified in the study, which together drive transcriptional activation of virulence genes. This coordinated response equips the bacterium to colonise host tissues and evade immune defences.

“Conformational changes in LvrB disrupt its symmetry, thereby activating the protein,” said Agustoni.

“In its on state, LvrB can transfer the signal to its partner protein, which allows activation of virulence genes that support bacterial spread in the body,” he said.

The findings suggest that pharmacological strategies to stabilise LvrB in its inactive conformation could suppress virulence without directly targeting bacterial viability. Such an approach may reduce selective pressure that typically drives antibiotic resistance. By interfering with regulatory pathways rather than essential cellular processes, it may prove possible to disarm pathogens while preserving the host microbiome.

Beyond leptospirosis, the study has broader implications for microbiology and infectious disease research. Proteins related to LvrB exist across a wide range of bacterial species, including pathogens that affect humans, livestock and crops. The structural and mechanistic principles identified here therefore provide a template to investigate similar signalling systems in other organisms.

“Our findings lay the foundation for uncovering a plethora of unexplored cellular processes and will support the development of novel antibiotics as well as agrochemicals,” said Hiller.

The work has reinforced the importance of structural biology to decode complex regulatory systems in pathogens. By mapping how molecular switches control virulence, researchers have begun to identify points of intervention that extend beyond conventional antimicrobial approaches.

For further reading please visit: 10.1038/s41467-026-71783-4