The critical journey: the role of clade and an adhesin in Leptospira kidney colonization

About This Grant

Project Summary Leptospirosis is the most widespread zoonotic disease, disproportionately affecting resource-limited populations and causing significant morbidity and mortality worldwide. Disease ranges from asymptomatic colonization to multiorgan dysfunction and hemorrhage. Leptospirosis is caused by pathogenic species of the genus Leptospira. No human vaccines are approved for use in the United States, and antibiotics are only effective when administered early, but delays due to non-specific early symptoms make treatment challenging. Novel strategies are needed to combat disease and transmission. Leptospira colonize the renal proximal tubules in reservoir hosts and are intermittently shed in the urine. Humans are accidental hosts and acquire infection through contact with infected animals or contaminated environmental sources. Following exposure, Leptospira spread through the bloodstream and colonize the proximal tubules of the kidney. The mechanisms of kidney adhesion remain poorly understood, making it crucial to define these pathways for the development of targeted antibacterial strategies. The central hypothesis of this proposal is that pathogenic Leptospira species (spp.) bind specific kidney cell types through LIC13411-cadherin interactions. Leptospira spp. are categorized into pathogenic (P) and saprophytic (S) clades, with four subclades (P1, P2, S1, and S2), each with distinct pathogenic potentials. While these subclades have been phylogenetically characterized, their functional differences in adhesion, colonization, and host-cell interactions remain unstudied. In this proposal, we will define the ability of species from each Leptospira subclade to bind specific cell types, including glomerular endothelial cells, podocytes, parietal epithelial cells, and proximal tubule epithelial cells. This will provide the first detailed understanding of Leptospira interactions with distinct kidney cell types encountered during infection – a previously unexplored area. One key aspect of bacterial pathogenesis is the ability of bacteria to bind to host cells and tissues, mediated by adhesins. The candidate adhesin LIC13411, identified from pathogenic Leptospira via a phage display selection, facilitates binding to host cells and cadherins and enhances tropism for the kidney in a short-term murine model of hematogenous dissemination. LIC13411 homologs are present across Leptospira subclades, yet their functional conservation and divergence remain unexplored. We will define the ability of LIC13411 homologs to bind kidney cells and cadherins and assess their role in vivo. By correlating the sequence variations of these homologs with binding data, we will determine the conservation of LIC13411 and identify key residues and domains crucial for its activity. Taken together, this work will define species- and adhesin-specific interactions, offering new insight into the evolution of Leptospira. Ultimately, these findings will advance our understanding of the pathogenesis of this zoonotic disease, thus informing the development of novel vaccine and therapeutic strategies to combat this potentially fatal infection.