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      Complement inhibition by Sarcoptes scabiei protects Streptococcus pyogenes - An in vitro study to unravel the molecular mechanisms behind the poorly understood predilection of S. pyogenes to infect mite-induced skin lesions

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          Abstract

          Background

          On a global scale scabies is one of the most common dermatological conditions, imposing a considerable economic burden on individuals, communities and health systems. There is substantial epidemiological evidence that in tropical regions scabies is often causing pyoderma and subsequently serious illness due to invasion by opportunistic bacteria. The health burden due to complicated scabies causing cellulitis, bacteraemia and sepsis, heart and kidney diseases in resource-poor communities is extreme. Co-infections of group A streptococcus (GAS) and scabies mites is a common phenomenon in the tropics. Both pathogens produce multiple complement inhibitors to overcome the host innate defence. We investigated the relative role of classical (CP), lectin (LP) and alternative pathways (AP) towards a pyodermic GAS isolate 88/30 in the presence of a scabies mite complement inhibitor, SMSB4.

          Methodology/Principal findings

          Opsonophagocytosis assays in fresh blood showed baseline immunity towards GAS. The role of innate immunity was investigated by deposition of the first complement components of each pathway, specifically C1q, FB and MBL from normal human serum on GAS. C1q deposition was the highest followed by FB deposition while MBL deposition was undetectable, suggesting that CP and AP may be mainly activated by GAS. We confirmed this result using sera depleted of either C1q or FB, and serum deficient in MBL. Recombinant SMSB4 was produced and purified from Pichia pastoris. SMSB4 reduced the baseline immunity against GAS by decreasing the formation of CP- and AP-C3 convertases, subsequently affecting opsonisation and the release of anaphylatoxin.

          Conclusions/Significance

          Our results indicate that the complement-inhibitory function of SMSB4 promotes the survival of GAS in vitro and inferably in the microenvironment of the mite-infested skin. Understanding the tripartite interactions between host, parasite and microbial pathogens at a molecular level may serve as a basis to develop improved intervention strategies targeting scabies and associated bacterial infections.

          Author summary

          The molecular mechanisms that underpin the link between scabies and bacterial pathogens were unknown. We proposed that scabies mites play a role in the establishment, proliferation and transmission of opportunistic pathogens. We investigated here the synergy between mites and one of the most recognised mite associated pathogens, Streptococcus pyogenes. As part of the innate immune response mammals have a pre-programmed ability to recognise and immediately act against substances derived from fungal and bacterial microorganisms. This is mediated through a sequential biochemical cascade involving over 30 different proteins (complement system) which as a result of signal amplification triggers a rapid killing response. The complement cascade produces peptides that attract immune cells, increases vascular permeability, coats (opsonises) the surfaces of a pathogen, marking it for destruction, and directly disrupts foreign plasma membranes. To prevent complement mediated damage of their gut cells, scabies mites secrete several classes of complement inhibiting proteins into the mite gut and excrete them into the epidermal mite burrows. Furthermore, these inhibitors also provide protection for S. pyogenes. We verified here specifically the impact of the mite complement inhibitor SMSB4, to identify the molecular mechanisms behind the long recognised tendency of S. pyogenes to infect mite-induced skin lesions.

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          Most cited references62

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          The global burden of group A streptococcal diseases.

          The global burden of disease caused by group A streptococcus (GAS) is not known. We review recent population-based data to estimate the burden of GAS diseases and highlight deficiencies in the available data. We estimate that there are at least 517,000 deaths each year due to severe GAS diseases (eg, acute rheumatic fever, rheumatic heart disease, post-streptococcal glomerulonephritis, and invasive infections). The prevalence of severe GAS disease is at least 18.1 million cases, with 1.78 million new cases each year. The greatest burden is due to rheumatic heart disease, with a prevalence of at least 15.6 million cases, with 282,000 new cases and 233,000 deaths each year. The burden of invasive GAS diseases is unexpectedly high, with at least 663,000 new cases and 163,000 deaths each year. In addition, there are more than 111 million prevalent cases of GAS pyoderma, and over 616 million incident cases per year of GAS pharyngitis. Epidemiological data from developing countries for most diseases is poor. On a global scale, GAS is an important cause of morbidity and mortality. These data emphasise the need to reinforce current control strategies, develop new primary prevention strategies, and collect better data from developing countries.
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            Complement System Part I – Molecular Mechanisms of Activation and Regulation

            Complement is a complex innate immune surveillance system, playing a key role in defense against pathogens and in host homeostasis. The complement system is initiated by conformational changes in recognition molecular complexes upon sensing danger signals. The subsequent cascade of enzymatic reactions is tightly regulated to assure that complement is activated only at specific locations requiring defense against pathogens, thus avoiding host tissue damage. Here, we discuss the recent advances describing the molecular and structural basis of activation and regulation of the complement pathways and their implication on physiology and pathology. This article will review the mechanisms of activation of alternative, classical, and lectin pathways, the formation of C3 and C5 convertases, the action of anaphylatoxins, and the membrane-attack-complex. We will also discuss the importance of structure–function relationships using the example of atypical hemolytic uremic syndrome. Lastly, we will discuss the development and benefits of therapies using complement inhibitors.
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              A systematic and functional classification of Streptococcus pyogenes that serves as a new tool for molecular typing and vaccine development.

              Streptococcus pyogenes ranks among the main causes of mortality from bacterial infections worldwide. Currently there is no vaccine to prevent diseases such as rheumatic heart disease and invasive streptococcal infection. The streptococcal M protein that is used as the substrate for epidemiological typing is both a virulence factor and a vaccine antigen. Over 220 variants of this protein have been described, making comparisons between proteins difficult, and hindering M protein-based vaccine development. A functional classification based on 48 emm-clusters containing closely related M proteins that share binding and structural properties is proposed. The need for a paradigm shift from type-specific immunity against S. pyogenes to emm-cluster based immunity for this bacterium should be further investigated. Implementation of this emm-cluster-based system as a standard typing scheme for S. pyogenes will facilitate the design of future studies of M protein function, streptococcal virulence, epidemiological surveillance, and vaccine development. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Negl Trop Dis
                PLoS Negl Trop Dis
                plos
                plosntds
                PLoS Neglected Tropical Diseases
                Public Library of Science (San Francisco, CA USA )
                1935-2727
                1935-2735
                9 March 2017
                March 2017
                : 11
                : 3
                : e0005437
                Affiliations
                [001]QIMR Berghofer Medical Research Institute, Infectious Diseases Department, Herston, Brisbane, Australia
                Johns Hopkins Bloomberg School of Public Health, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                • Conceptualization: KF KSS PMS.

                • Data curation: PMS KF.

                • Formal analysis: PMS.

                • Funding acquisition: KF.

                • Investigation: PMS LDC HCL.

                • Methodology: KF PMS KSS.

                • Project administration: KF PMS.

                • Resources: KF.

                • Supervision: KF.

                • Validation: KF PMS KSS.

                • Visualization: PMS KF.

                • Writing – original draft: PMS KF.

                • Writing – review & editing: KF PMS KSS.

                Author information
                http://orcid.org/0000-0003-3408-3337
                Article
                PNTD-D-16-02278
                10.1371/journal.pntd.0005437
                5360341
                28278252
                85f499e2-8be3-4b76-a98d-24715f2a2768
                © 2017 Swe 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.

                History
                : 21 December 2016
                : 25 February 2017
                Page count
                Figures: 5, Tables: 0, Pages: 20
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100000925, National Health and Medical Research Council;
                Award ID: Project Grant ID 1067192
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100000923, Australian Research Council;
                Award ID: FT130101875 (Future Fellowship)
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100001030, National Heart Foundation of Australia;
                Award ID: Australian Indigenous Scholarship
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100000937, Department of Education, Employment and Workplace Relations, Australian Government;
                Award ID: Indigenous Cadetship Support
                Award Recipient :
                This research was supported by funding from the Australian Government National Health and Medical Research Council (Project Grant ID 1067192). KF was supported by an Australian Research Council Future Fellowship (FT130101875). LDC was supported by an Indigenous Cadetship provided by the Australian Government, Department of Education, Employment and Workplace relations and by an Australian Indigenous Scholarship provided by the National Heart Foundation, Australia. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
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                2017-03-21
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                Infectious disease & Microbiology
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