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The Role of Streptococcal and Staphylococcal Exotoxins and Proteases in Human Necrotizing Soft Tissue Infections
toxins Review The Role of Streptococcal and Staphylococcal Exotoxins and Proteases in Human Necrotizing Soft Tissue Infections Patience Shumba 1, Srikanth Mairpady Shambat 2 and Nikolai Siemens 1,* 1 Center for Functional Genomics of Microbes, Department of Molecular Genetics and Infection Biology, University of Greifswald, D-17489 Greifswald, Germany; [email protected] 2 Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, CH-8091 Zurich, Switzerland; [email protected] * Correspondence: [email protected]; Tel.: +49-3834-420-5711 Received: 20 May 2019; Accepted: 10 June 2019; Published: 11 June 2019 Abstract: Necrotizing soft tissue infections (NSTIs) are critical clinical conditions characterized by extensive necrosis of any layer of the soft tissue and systemic toxicity. Group A streptococci (GAS) and Staphylococcus aureus are two major pathogens associated with monomicrobial NSTIs. In the tissue environment, both Gram-positive bacteria secrete a variety of molecules, including pore-forming exotoxins, superantigens, and proteases with cytolytic and immunomodulatory functions. The present review summarizes the current knowledge about streptococcal and staphylococcal toxins in NSTIs with a special focus on their contribution to disease progression, tissue pathology, and immune evasion strategies. Keywords: Streptococcus pyogenes; group A streptococcus; Staphylococcus aureus; skin infections; necrotizing soft tissue infections; pore-forming toxins; superantigens; immunomodulatory proteases; immune responses Key Contribution: Group A streptococcal and Staphylococcus aureus toxins manipulate host physiological and immunological responses to promote disease severity and progression. 1. Introduction Necrotizing soft tissue infections (NSTIs) are rare and represent a more severe rapidly progressing form of soft tissue infections that account for significant morbidity and mortality [1]. -
How Do Pathogenic Microorganisms Develop Cross-Kingdom Host Jumps? Peter Van Baarlen1, Alex Van Belkum2, Richard C
Molecular mechanisms of pathogenicity: how do pathogenic microorganisms develop cross-kingdom host jumps? Peter van Baarlen1, Alex van Belkum2, Richard C. Summerbell3, Pedro W. Crous3 & Bart P.H.J. Thomma1 1Laboratory of Phytopathology, Wageningen University, Wageningen, The Netherlands; 2Department of Medical Microbiology and Infectious Diseases, Erasmus MC, University Medical Centre Rotterdam, Rotterdam, The Netherlands; and 3CBS Fungal Biodiversity Centre, Utrecht, The Netherlands Correspondence: Bart P.H.J. Thomma, Abstract Downloaded from https://academic.oup.com/femsre/article/31/3/239/2367343 by guest on 27 September 2021 Laboratory of Phytopathology, Wageningen University, Binnenhaven 5, 6709 PD It is common knowledge that pathogenic viruses can change hosts, with avian Wageningen, The Netherlands. Tel.: 10031 influenza, the HIV, and the causal agent of variant Creutzfeldt–Jacob encephalitis 317 484536; fax: 10031 317 483412; as well-known examples. Less well known, however, is that host jumps also occur e-mail: [email protected] with more complex pathogenic microorganisms such as bacteria and fungi. In extreme cases, these host jumps even cross kingdom of life barriers. A number of Received 3 July 2006; revised 22 December requirements need to be met to enable a microorganism to cross such kingdom 2006; accepted 23 December 2006. barriers. Potential cross-kingdom pathogenic microorganisms must be able to First published online 26 February 2007. come into close and frequent contact with potential hosts, and must be able to overcome or evade host defences. Reproduction on, in, or near the new host will DOI:10.1111/j.1574-6976.2007.00065.x ensure the transmission or release of successful genotypes. -
Nasopharyngeal Infection by Streptococcus Pyogenes Requires Superantigen-Responsive Vβ-Specific T Cells
Nasopharyngeal infection by Streptococcus pyogenes requires superantigen-responsive Vβ-specific T cells Joseph J. Zeppaa, Katherine J. Kaspera, Ivor Mohorovica, Delfina M. Mazzucaa, S. M. Mansour Haeryfara,b,c,d, and John K. McCormicka,c,d,1 aDepartment of Microbiology and Immunology, Schulich School of Medicine & Dentistry, Western University, London, ON N6A 5C1, Canada; bDepartment of Medicine, Division of Clinical Immunology & Allergy, Schulich School of Medicine & Dentistry, Western University, London, ON N6A 5A5, Canada; cCentre for Human Immunology, Western University, London, ON N6A 5C1, Canada; and dLawson Health Research Institute, London, ON N6C 2R5, Canada Edited by Philippa Marrack, Howard Hughes Medical Institute, National Jewish Health, Denver, CO, and approved July 14, 2017 (received for review January 18, 2017) The globally prominent pathogen Streptococcus pyogenes secretes context of invasive streptococcal disease is extremely dangerous, potent immunomodulatory proteins known as superantigens with a mortality rate of over 30% (10). (SAgs), which engage lateral surfaces of major histocompatibility The role of SAgs in severe human infections has been well class II molecules and T-cell receptor (TCR) β-chain variable domains established (5, 11, 12), and specific MHC-II haplotypes are known (Vβs). These interactions result in the activation of numerous Vβ- risk factors for the development of invasive streptococcal disease specific T cells, which is the defining activity of a SAg. Although (13), an outcome that has been directly linked to SAgs (14, 15). streptococcal SAgs are known virulence factors in scarlet fever However, how these exotoxins contribute to superficial disease and and toxic shock syndrome, mechanisms by how SAgs contribute colonization is less clear. -
Impact of Bacterial Toxins in the Lungs
toxins Review Impact of Bacterial Toxins in the Lungs 1,2,3, , 4,5, 3 2 Rudolf Lucas * y, Yalda Hadizamani y, Joyce Gonzales , Boris Gorshkov , Thomas Bodmer 6, Yves Berthiaume 7, Ueli Moehrlen 8, Hartmut Lode 9, Hanno Huwer 10, Martina Hudel 11, Mobarak Abu Mraheil 11, Haroldo Alfredo Flores Toque 1,2, 11 4,5,12,13, , Trinad Chakraborty and Jürg Hamacher * y 1 Pharmacology and Toxicology, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA; hfl[email protected] 2 Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA; [email protected] 3 Department of Medicine and Division of Pulmonary Critical Care Medicine, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA; [email protected] 4 Lungen-und Atmungsstiftung, Bern, 3012 Bern, Switzerland; [email protected] 5 Pneumology, Clinic for General Internal Medicine, Lindenhofspital Bern, 3012 Bern, Switzerland 6 Labormedizinisches Zentrum Dr. Risch, Waldeggstr. 37 CH-3097 Liebefeld, Switzerland; [email protected] 7 Department of Medicine, Faculty of Medicine, Université de Montréal, Montréal, QC H3T 1J4, Canada; [email protected] 8 Pediatric Surgery, University Children’s Hospital, Zürich, Steinwiesstrasse 75, CH-8032 Zürch, Switzerland; [email protected] 9 Insitut für klinische Pharmakologie, Charité, Universitätsklinikum Berlin, Reichsstrasse 2, D-14052 Berlin, Germany; [email protected] 10 Department of Cardiothoracic Surgery, Voelklingen Heart Center, 66333 -
Chemical Strategies to Target Bacterial Virulence
Review pubs.acs.org/CR Chemical Strategies To Target Bacterial Virulence † ‡ ‡ † ‡ § ∥ Megan Garland, , Sebastian Loscher, and Matthew Bogyo*, , , , † ‡ § ∥ Cancer Biology Program, Department of Pathology, Department of Microbiology and Immunology, and Department of Chemical and Systems Biology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California 94305, United States ABSTRACT: Antibiotic resistance is a significant emerging health threat. Exacerbating this problem is the overprescription of antibiotics as well as a lack of development of new antibacterial agents. A paradigm shift toward the development of nonantibiotic agents that target the virulence factors of bacterial pathogens is one way to begin to address the issue of resistance. Of particular interest are compounds targeting bacterial AB toxins that have the potential to protect against toxin-induced pathology without harming healthy commensal microbial flora. Development of successful antitoxin agents would likely decrease the use of antibiotics, thereby reducing selective pressure that leads to antibiotic resistance mutations. In addition, antitoxin agents are not only promising for therapeutic applications, but also can be used as tools for the continued study of bacterial pathogenesis. In this review, we discuss the growing number of examples of chemical entities designed to target exotoxin virulence factors from important human bacterial pathogens. CONTENTS 3.5.1. C. diphtheriae: General Antitoxin Strat- egies 4435 1. Introduction 4423 3.6. Pseudomonas aeruginosa 4435 2. How Do Bacterial AB Toxins Work? 4424 3.6.1. P. aeruginosa: Inhibitors of ADP Ribosyl- 3. Small-Molecule Antivirulence Agents 4426 transferase Activity 4435 3.1. Clostridium difficile 4426 3.7. Bordetella pertussis 4436 3.1.1. C. -
Staphylococcal Enterotoxins
Toxins 2010, 2, 2177-2197; doi:10.3390/toxins2082177 OPEN ACCESS toxins ISSN 2072-6651 www.mdpi.com/journal/toxins Review Staphylococcal Enterotoxins Irina V. Pinchuk 1, Ellen J. Beswick 2 and Victor E. Reyes 3,* 1 Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555-0655, USA; E-Mail: [email protected] 2 Department of Molecular Genetics & Microbiology, University of New Mexico, Albuquerque, NM 87131, USA; E-Mail: [email protected] 3 Departments of Pediatrics and Microbiology & Immunology, University of Texas Medical Branch, Galveston, TX 77555-0366, USA * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +1-409-772-3824; Fax: +1-409-772-1761. Received: 29 June 2010; in revised form: 9 August 2010 / Accepted: 12 August 2010 / Published: 18 August 2010 Abstract: Staphylococcus aureus (S. aureus) is a Gram positive bacterium that is carried by about one third of the general population and is responsible for common and serious diseases. These diseases include food poisoning and toxic shock syndrome, which are caused by exotoxins produced by S. aureus. Of the more than 20 Staphylococcal enterotoxins, SEA and SEB are the best characterized and are also regarded as superantigens because of their ability to bind to class II MHC molecules on antigen presenting cells and stimulate large populations of T cells that share variable regions on the chain of the T cell receptor. The result of this massive T cell activation is a cytokine bolus leading to an acute toxic shock. These proteins are highly resistant to denaturation, which allows them to remain intact in contaminated food and trigger disease outbreaks. -
The Evolving Field of Biodefence: Therapeutic Developments and Diagnostics
REVIEWS THE EVOLVING FIELD OF BIODEFENCE: THERAPEUTIC DEVELOPMENTS AND DIAGNOSTICS James C. Burnett*, Erik A. Henchal‡,Alan L. Schmaljohn‡ and Sina Bavari‡ Abstract | The threat of bioterrorism and the potential use of biological weapons against both military and civilian populations has become a major concern for governments around the world. For example, in 2001 anthrax-tainted letters resulted in several deaths, caused widespread public panic and exerted a heavy economic toll. If such a small-scale act of bioterrorism could have such a huge impact, then the effects of a large-scale attack would be catastrophic. This review covers recent progress in developing therapeutic countermeasures against, and diagnostics for, such agents. BACILLUS ANTHRACIS Microorganisms and toxins with the greatest potential small-molecule inhibitors, and a brief review of anti- The causative agent of anthrax for use as biological weapons have been categorized body development and design against biotoxins is and a Gram-positive, spore- using the scale A–C by the Centers for Disease Control mentioned in TABLE 1. forming bacillus. This aerobic and Prevention (CDC). This review covers the discovery organism is non-motile, catalase and challenges in the development of therapeutic coun- Anthrax toxin. The toxin secreted by BACILLUS ANTHRACIS, positive and forms large, grey–white to white, non- termeasures against select microorganisms and toxins ANTHRAX TOXIN (ATX), possesses the ability to impair haemolytic colonies on sheep from these categories. We also cover existing antibiotic innate and adaptive immune responses1–3,which in blood agar plates. treatments, and early detection and diagnostic strategies turn potentiates the bacterial infection. -
Virulence Factors and Their Mechanisms of Action: the View from a Damage–Response Framework Arturo Casadevall and Liise-Anne Pirofski
S2 Q IWA Publishing 2009 Journal of Water and Health | 07.S1 | 2009 Virulence factors and their mechanisms of action: the view from a damage–response framework Arturo Casadevall and Liise-anne Pirofski ABSTRACT The virulence factor concept has been a powerful engine in driving research and the intellectual Arturo Casadevall (corresponding author) Liise-anne Pirofski flow in the fields of microbial pathogenesis and infectious diseases. This review analyzes Division of Infectious Diseases, virulence factors from the viewpoint of the damage–response framework of microbial Department of Medicine and the Department of Microbiology and Immunology of the Albert pathogenesis, which defines virulence factor as microbial components that can damage a Einstein College of Medicine, 1300 Morris Park Avenue, susceptible host. At a practical level, the finding that effective immune responses often target Bronx NY 10461, USA virulence factors provides a roadmap for future vaccine design. However, there are significant Tel.: +1 718 430 2215 limitations to this concept, which are rooted in the inability to define virulence and virulence Fax: +1 718 430 8968 E-mail: [email protected] factors in the absence of host factors and the host response. In fact, this concept appears to work best for certain types of bacterial pathogens, being less well suited for viruses and commensal organisms with pathogenic potential. Key words | damage–response framework, microbe, pathogen, pathogenicity, virulence, virulence factor INTRODUCTION The idea that pathogenic microbes are endowed with understanding of microbial virulence. In this paper, we certain components that confer upon them the capacity review the historical context for the emergence of the for virulence is the central theme of the virulence factor virulence factor concept and then consider it from concept. -
Responses to Bacterial Superantigens HLA Class II Polymorphisms Determine
The Journal of Immunology HLA Class II Polymorphisms Determine Responses to Bacterial Superantigens1 Martin Llewelyn,* Shiranee Sriskandan,* Mark Peakman,† David R. Ambrozak,‡ Daniel C. Douek,‡ William W. Kwok,§ Jonathan Cohen,*¶ and Daniel M. Altmann2* The excessive immunological response triggered by microbial superantigens has been implicated in the etiology of a wide range of human diseases but has been most clearly defined for the staphylococcal and streptococcal toxic shock syndromes. Because MHC class II presentation of superantigens to T cells is not MHC-restricted, the possibility that HLA polymorphisms could influence superantigenicity, and thus clinical susceptibility to the toxicity of individual superantigens, has received little attention. In this study, we demonstrate that binding of streptococcal and staphylococcal superantigens to HLA class II is influenced by allelic differences in class II. For the superantigen streptococcal pyrogenic exotoxin A, class II binding is dependent on DQ ␣-chain polymorphisms such that HLA-DQA1*01 ␣-chains show greater binding than DQA1*03/05 ␣-chains. The functional implications of differential binding on T cell activation were investigated in various experimental systems using human T cells and murine V8.2 transgenic cells as responders. These studies showed quantitative and qualitative differences resulting from differential HLA-DQ binding. We observed changes in T cell proliferation and cytokine production, and in the V specific changes in T cell repertoire that have hitherto been regarded as a defining feature of an individual superantigen. Our observations reveal a mechanism for the different outcomes seen following infection by toxigenic bacteria. The Journal of Immunology, 2004, 172: 1719–1726. uperantigens (SAgs)3 are potent immunostimulatory pro- of all T cells. -
Pathogenesis of Bacterial Pathogens
FMM/RAS/298: Strengthening capacities, policies and national action plans on prudent and responsible use of antimicrobials in fisheries Bacterial Pathogenesis Larry A. Hanson [email protected] Aquatic AMR Workshop 1: 10-11 April 2017, Mangalore, India Host-Parasite Relationships: Pathogenesis of Infections In any host-pathogen encounter, there are two determinants of the outcome: 1. Virulence of the parasite 2. Resistance of the host In some cases, the host-pathogen relationship is very complex: -Commensal but opportunistic will take advantage of weakened host and invade tissues setting up a potentially life- threatening infection Examples include motile Aeromonads- natural inhabitants of intestine but cause septicemia when fish is immune suppressed o Bacteria cause disease by 2 basic mechanisms: 1-Direct damage of host cells 2-Indirectly by stimulating exaggerated host inflammatory/immune response Virulence factors are molecular components expressed by a pathogen that increases its ability to cause disease Virulence factors can be divided into two categories: • 1. Those that cause damage to the host (toxins) • 2. Those that do not directly damage the host but promote colonization and survival of infecting bacteria A. Bacterial toxins 1. Exotoxin: protein molecule liberated from intact living bacterium. a. They are antigenic and can elicit protective antitoxic antibodies. Many of these toxins can be converted to nontoxic immunizing agents termed toxoids. b. Three roles of exotoxins in disease: i. Ingestion of preformed toxin (botulism) ii. Colonization of wound or surface followed by toxin production (cholera and diphtheria toxins) iii. Exotoxin produced by bacteria in tissues to aid growth and spread (Clostridium perfringens alpha-toxin) d. -
Streptococcal Pyrogenic Exotoxin C Discrimination by the Bacterial Superantigen -Chain Engagement and Allelic Α Molecular Requi
Molecular Requirements for MHC Class II α -Chain Engagement and Allelic Discrimination by the Bacterial Superantigen Streptococcal Pyrogenic Exotoxin C This information is current as of October 5, 2018. Katherine J. Kasper, Wang Xi, A. K. M. Nur-ur Rahman, Mohammed M. Nooh, Malak Kotb, Eric J. Sundberg, Joaquín Madrenas and John K. McCormick J Immunol 2008; 181:3384-3392; ; doi: 10.4049/jimmunol.181.5.3384 Downloaded from http://www.jimmunol.org/content/181/5/3384 References This article cites 62 articles, 27 of which you can access for free at: http://www.jimmunol.org/content/181/5/3384.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on October 5, 2018 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2008 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Molecular Requirements for MHC Class II ␣-Chain Engagement and Allelic Discrimination by the Bacterial Superantigen Streptococcal Pyrogenic Exotoxin C1 Katherine J. -
Structural Basis of the Pore-Forming Toxin/Membrane Interaction
toxins Review Structural Basis of the Pore-Forming Toxin/Membrane Interaction Yajuan Li 1, Yuelong Li 2, Hylemariam Mihiretie Mengist 2, Cuixiao Shi 1, Caiying Zhang 2 , Bo Wang 1, Tingting Li 1, Ying Huang 1, Yuanhong Xu 1,* and Tengchuan Jin 2,* 1 Department of Clinical Laboratory, the First Affiliated Hospital of Anhui Medical University, Hefei 230022, China; [email protected] (Y.L.); [email protected] (C.S.); [email protected] (B.W.); [email protected] (T.L.); [email protected] (Y.H.) 2 Hefei National Laboratory for Physical Sciences at Microscale, Laboratory of Structural Immunology, CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, School of Basic Medical Sciences, University of Science and Technology of China, Hefei 230027, China; [email protected] (Y.L.); [email protected] (H.M.M.); [email protected] (C.Z.) * Correspondence: [email protected] (Y.X.); [email protected] (T.J.); Tel.: +86-13505694447 (Y.X.); +86-17605607323 (T.J.) Abstract: With the rapid growth of antibiotic-resistant bacteria, it is urgent to develop alternative therapeutic strategies. Pore-forming toxins (PFTs) belong to the largest family of virulence factors of many pathogenic bacteria and constitute the most characterized classes of pore-forming proteins (PFPs). Recent studies revealed the structural basis of several PFTs, both as soluble monomers, and transmembrane oligomers. Upon interacting with host cells, the soluble monomer of bacterial PFTs assembles into transmembrane oligomeric complexes that insert into membranes and affect target cell-membrane permeability, leading to diverse cellular responses and outcomes.