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      Borrelia burgdorferi BBK32 Inhibits the Classical Pathway by Blocking Activation of the C1 Complement Complex

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Pathogens that traffic in blood, lymphatics, or interstitial fluids must adopt strategies to evade innate immune defenses, notably the complement system. Through recruitment of host regulators of complement to their surface, many pathogens are able to escape complement-mediated attack. The Lyme disease spirochete, Borrelia burgdorferi, produces a number of surface proteins that bind to factor H related molecules, which function as the dominant negative regulator of the alternative pathway of complement. Relatively less is known about how B. burgdorferi evades the classical pathway of complement despite the observation that some sensu lato strains are sensitive to classical pathway activation. Here we report that the borrelial lipoprotein BBK32 potently and specifically inhibits the classical pathway by binding with high affinity to the initiating C1 complex of complement. In addition, B. burgdorferi cells that produce BBK32 on their surface bind to both C1 and C1r and a serum sensitive derivative of B. burgdorferi is protected from killing via the classical pathway in a BBK32-dependent manner. Subsequent biochemical and biophysical approaches localized the anti-complement activity of BBK32 to its globular C-terminal domain. Mechanistic studies reveal that BBK32 acts by entrapping C1 in its zymogen form by binding and inhibiting the C1 subcomponent, C1r, which serves as the initiating serine protease of the classical pathway. To our knowledge this is the first report of a spirochetal protein acting as a direct inhibitor of the classical pathway and is the only example of a biomolecule capable of specifically and noncovalently inhibiting C1/C1r. By identifying a unique mode of complement evasion this study greatly enhances our understanding of how pathogens subvert and potentially manipulate host innate immune systems.

          Author Summary

          The human complement system is a connected network of blood proteins capable of recognizing and eliminating microbial intruders. To avoid the destructive force of complement activation, many microorganisms that enter the bloodstream express molecules that disrupt key steps of the complement cascade by interacting with specific complement components. In this study we show that the causative agent of Lyme disease, Borrelia burgdorferi, expresses a surface-protein termed BBK32 that targets and inhibits the first component of complement, designated C1. Upon binding to human C1, BBK32 traps this initiating protease complex of the classical pathway of complement in an inactive state, and prevents the downstream proteolytic events of the pathway. Our study defines a new mechanism by which microbes are able to escape the human innate immune system and identifies complement protease C1r as a previously unknown target of bacterial anti-complement molecules. Thus, discovery of the complement inhibitory activity of the borrelial protein BBK32 significantly advances our understanding of how disease-causing bacteria survive in immune competent hosts.

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          Most cited references 95

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          Cleavage of structural proteins during the assembly of the head of bacteriophage T4.

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            Complement: a key system for immune surveillance and homeostasis.

            Nearly a century after the significance of the human complement system was recognized, we have come to realize that its functions extend far beyond the elimination of microbes. Complement acts as a rapid and efficient immune surveillance system that has distinct effects on healthy and altered host cells and foreign intruders. By eliminating cellular debris and infectious microbes, orchestrating immune responses and sending 'danger' signals, complement contributes substantially to homeostasis, but it can also take action against healthy cells if not properly controlled. This review describes our updated view of the function, structure and dynamics of the complement network, highlights its interconnection with immunity at large and with other endogenous pathways, and illustrates its multiple roles in homeostasis and disease.
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              Lyme borreliosis.

              Lyme borreliosis (Lyme disease) is caused by spirochaetes of the Borrelia burgdorferi sensu lato species complex, which are transmitted by ticks. The most common clinical manifestation is erythema migrans, which eventually resolves, even without antibiotic treatment. However, the infecting pathogen can spread to other tissues and organs, causing more severe manifestations that can involve a patient's skin, nervous system, joints, or heart. The incidence of this disease is increasing in many countries. Laboratory evidence of infection, mainly serology, is essential for diagnosis, except in the case of typical erythema migrans. Diagnosed cases are usually treated with antibiotics for 2-4 weeks and most patients make an uneventful recovery. No convincing evidence exists to support the use of antibiotics for longer than 4 weeks, or for the persistence of spirochaetes in adequately treated patients. Prevention is mainly accomplished by protecting against tick bites. There is no vaccine available for human beings. Copyright © 2012 Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                plospath
                PLoS Pathogens
                Public Library of Science (San Francisco, CA USA )
                1553-7366
                1553-7374
                25 January 2016
                January 2016
                : 12
                : 1
                Affiliations
                [1 ]Department of Biochemistry and Molecular Biophysics, Kansas State University, Manhattan, Kansas, United States of America
                [2 ]Center for Infectious and Inflammatory Diseases, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, Texas, United States of America
                [3 ]Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas A&M Health Science Center, Bryan, Texas, United States of America
                University of Montana, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: BLG HZ BW MH JTS. Performed the experiments: BLG HZ BW. Analyzed the data: BLG HZ BW MH JTS. Wrote the paper: BLG HZ MH JTS.

                [¤]

                Current address: Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA 02111, United States of America

                Article
                PPATHOGENS-D-15-02272
                10.1371/journal.ppat.1005404
                4725857
                26808924
                © 2016 Garcia et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Counts
                Figures: 10, Tables: 2, Pages: 28
                Product
                Funding
                This work was supported by the National Institute of Health Grants AI058086 (to JTS and MH) AI119821 (to JTS and MH), and AI113552 (to support BLG), as well as a Pre-Doctoral Training Grant Award from the Texas A&M Health Science Center, College of Medicine (to support HZ). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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