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research-article
Author(s):
Karen V. Evangelista 1 ,
Beth Hahn 2 ,
Elsio A. Wunder Jr 3 ,
Albert I. Ko 3 ,
David A. Haake 4 , 5 ,
Jenifer Coburn 1 , 2 , *
Publication date (Electronic): 2 October 2014
Journal: PLoS Neglected Tropical Diseases
Publisher: Public Library of Science
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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 hom*ologue 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. Leptospirosis, caused by pathogenic species of the genus Leptospira, is an infectious disease that has emerged as a globally important health problem. Infection can either lead to mild illness or can progress to a severe disease form manifested by jaundice, kidney and liver dysfunction, and widespread blood vessel damage. 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. Using phage display, we were able to identify bacterial proteins that mediate the binding of the bacteria to host cells. One of the identified proteins, LIC11574, attaches to different types of host cells, and to VE-cadherin, a cell surface protein previously identified as receptor for disease-causing L. interrogans. All bacterial proteins identified were recognized by sera obtained from leptospirosis patients but not by sera from healthy individuals. Our findings may be of value in leptospirosis control and prevention, with these bacterial surface proteins as new targets for serodiagnosis and vaccine development. Abstract
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Most cited references69
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Leptospira and leptospirosis.
Ben Adler, Alejandro de la Peña Moctezuma (2010)
Leptospirosis is the most wide spread zoonosis worldwide; it is present in all continents except Antarctica and evidence for the carriage of Leptospira has been found in virtually all mammalian species examined. Humans most commonly become infected through occupational, recreational, or domestic contact with the urine of carrier animals, either directly or via contaminated water or soil. Leptospires are thin, helical bacteria classified into at least 12 pathogenic and 4 saprophytic species, with more than 250 pathogenic serovars. Immunity following infection is generally, but not exclusively, mediated by antibody against leptospiral LPS and restricted to antigenically related serovars. Vaccines currently available consist of killed whole cell bacterins which are used widely in animals, but less so in humans. Current work with recombinant protein antigens shows promise for the development of vaccines based on defined protective antigens. The cellular and molecular basis for virulence remains poorly understood, but comparative genomics of pathogenic and saprophytic species suggests that Leptospira expresses unique virulence determinants. However, the recent development of defined mutagenesis systems for Leptospira heralds the potential for gaining a much improved understanding of pathogenesis in leptospirosis. Copyright 2009 Elsevier B.V. All rights reserved.
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The role of adherens junctions and VE-cadherin in the control of vascular permeability.
Elisabetta Dejana, Fabrizio Orsenigo, Maria Grazia Lampugnani (2008)
Endothelial cells control the passage of plasma constituents and circulating cells from blood to the underlying tissues. This specialized function is lost or impaired in several pathological conditions - including inflammation, sepsis, ischemia and diabetes - which leads to severe, and sometimes fatal, organ dysfunction. Endothelial permeability is regulated in part by the dynamic opening and closure of cell-cell adherens junctions (AJs). In endothelial cells, AJs are largely composed of vascular endothelial cadherin (VE-cadherin), an endothelium-specific member of the cadherin family of adhesion proteins that binds, via its cytoplasmic domain, to several protein partners, including p120, beta-catenin and plakoglobin. Endogenous pathways that increase vascular permeability affect the function and organization of VE-cadherin and other proteins at AJs in diverse ways. For instance, several factors, including vascular endothelial growth factor (VEGF), induce the tyrosine phosphorylation of VE-cadherin, which accompanies an increase in vascular permeability and leukocyte diapedesis; in addition, the internalization and cleavage of VE-cadherin can cause AJs to be dismantled. From the knowledge of how AJ organization can be modulated, it is possible to formulate several pharmacological strategies to control the barrier function of the endothelium. We discuss the possible use of inhibitors of SRC and other kinases, of agents that increase cAMP levels, and of inhibitors of lytic enzymes as pharmacological tools for decreasing endothelial permeability.
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Leptospira: the dawn of the molecular genetics era for an emerging zoonotic pathogen.
Albert Ko, Cyrille Goarant, Mathieu Picardeau (2009)
Leptospirosis is a zoonotic disease that has emerged as an important cause of morbidity and mortality among impoverished populations. One hundred years after the discovery of the causative spirochaetal agent, little is understood about Leptospira spp. pathogenesis, which in turn has hampered the development of new intervention strategies to address this neglected disease. However, the recent availability of complete genome sequences for Leptospira spp. and the discovery of genetic tools for their transformation have led to important insights into the biology of these pathogens and their pathogenesis. We discuss the life cycle of the bacterium, the recent advances in our understanding and the implications for the future prevention of leptospirosis.
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Author and article information
Contributors
Pamela L. C. Small: Role: Editor
Journal
Journal ID (nlm-ta): PLoS Negl Trop Dis
Journal ID (iso-abbrev): PLoS Negl Trop Dis
Journal ID (publisher-id): plos
Journal ID (pmc): plosntds
Title: PLoS Neglected Tropical Diseases
Publisher: Public Library of Science (San Francisco, USA )
ISSN (Print): 1935-2727
ISSN (Electronic): 1935-2735
Publication date Collection: October 2014
Publication date (Electronic): 2 October 2014
Volume: 8
Issue: 10
Electronic Location Identifier: e3215
Affiliations
[1 ]Graduate Program in Microbiology, Immunology, and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
[2 ]Division of Infectious Diseases, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
[3 ]Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, Connecticut, United States of America
[4 ]Division of Infectious Diseases, VA Greater Los Angeles Healthcare System, Los Angeles, California, United States of America
Author notes
* E-mail: jcoburn@ 123456mcw.edu
Conceived and designed the experiments: KVE JC. Performed the experiments: KVE BH. Analyzed the data: KVE JC. Contributed reagents/materials/analysis tools: AIK EAW DAH. Contributed to the writing of the manuscript: KVE JC.
Article
Publisher ID: PNTD-D-14-01208
DOI: 10.1371/journal.pntd.0003215
PMC ID: 4183468
PubMed ID: 25275630
SO-VID: bfa60a5a-b3a8-4876-bf7d-2bb0da6e991f
Copyright statement: Copyright @ 2014
License:
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
History
Date received : 18 July 2014
Date accepted : 25 August 2014
Page count
Pages: 14
Funding
This work was supported by National Institutes of Health grants R21 AI077560, R56 AI087835, and R21 AI093509 to JC, R01 AI 034431 to DAH, R01 AI 052473, R01 TW009504, and U01 AI088752 to AIK, and by a Veterans Affairs Merit Review award to DAH. None of the funders had any role in the design or analysis of experiments, the preparation of the manuscript, or the decision to publish.
Categories
Subject: Research Article
Subject: Biology and Life Sciences
Subject: Microbiology
Subject: Bacteriology
Subject: Medical Microbiology
Subject: Veterinary Science
Subject: Veterinary Microbiology
Subject: Medicine and Health Sciences
Subject: Infectious Diseases
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