Abstract
Leptospirosis is a globally distributed bacterial infectious disease caused by pathogenic members of the genus Leptospira. Infection can lead to illness ranging from mild and non-specific to severe, with jaundice, kidney and liver dysfunction, and widespread endothelial damage. The adhesion of pathogenic Leptospira species (spp.), the causative agent of leptospirosis, to host tissue components is necessary for infection and pathogenesis. While it is well-established that extracellular matrix (ECM) components play a role in the interaction of the pathogen with host molecules, we have shown that pathogenic Leptospira interrogans binds to host cells more efficiently than to ECM components. Using in vitro phage display to select for phage clones that bind to EA.hy926 endothelial cells, we identified the putative lipoproteins LIC10508 and LIC13411, and the conserved hypothetical proteins LIC12341 and LIC11574, as candidate L. interrogans sv. Copenhageni st. Fiocruz L1–130 adhesins. Recombinant LIC11574, but not its L. biflexa homologue LBF1629, exhibited dose-dependent binding to both endothelial and epithelial cells. In addition, LIC11574 and LIC13411 bind to VE-cadherin, an endothelial cell receptor for L. interrogans. Extraction of bacteria with the non-ionic detergent Triton X-114 resulted in partitioning of the candidate adhesins to the detergent fraction, a likely indication that these proteins are outer membrane localized. All candidate adhesins were recognized by sera obtained from leptospirosis patients but not by sera from healthy individuals as assessed by western blot. This work has identified bacterial adhesins that are potentially involved in L. interrogans infection of the mammalian host, and through cadherin binding, may contribute to dissemination and vascular damage. Our findings may be of value in leptospirosis control and prevention, with the bacterial adhesins potentially serving as targets for development of diagnostics, therapeutics, and vaccines.
Highlights
Leptospirosis, caused by pathogenic species of the genus Leptospira, is the most widespread zoonosis and has emerged as a major public health problem worldwide, in the humid tropical and subtropical areas in developing countries
It is thought that the ability of the bacteria to recognize and bind to human and animal cells is important for Leptospira spp. to cause the disease
One of the identified proteins, LIC11574, attaches to different types of host cells, and to VEcadherin, a cell surface protein previously identified as receptor for disease-causing L. interrogans
Summary
Leptospirosis, caused by pathogenic species of the genus Leptospira, is the most widespread zoonosis and has emerged as a major public health problem worldwide, in the humid tropical and subtropical areas in developing countries. Specific groups at risk for infection include farmers, sewer workers, slaughterhouse workers, and veterinarians [1]. Outbreaks of this disease are associated with severe flooding events in urban slum areas [2,3,4]. Leptospira spp. can rapidly disseminate from the portal of entry to any tissue of the host, and persist in the proximal tubules of the kidney of reservoir hosts such as rodents. Leptospirosis is spread through the contact of mucous membranes, cuts, or abrasions with fresh water contaminated by the urine of infected animals [5,6,7]
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