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Immune Evasion by

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  • Authors: Nienke W. M. de Jong1, Kok P. M. van Kessel2, Jos A. G. van Strijp3
  • Editors: Vincent A. Fischetti4, Richard P. Novick5, Joseph J. Ferretti6, Daniel A. Portnoy7, Miriam Braunstein8, Julian I. Rood9
    Affiliations: 1: Department of Medical Microbiology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands; 2: Department of Medical Microbiology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands; 3: Department of Medical Microbiology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands; 4: The Rockefeller University, New York, NY; 5: Skirball Institute for Molecular Medicine, NYU Medical Center, New York, NY; 6: Department of Microbiology & Immunology, University of Oklahoma Health Science Center, Oklahoma City, OK; 7: Department of Molecular and Cellular Microbiology, University of California, Berkeley, Berkeley, CA; 8: Department of Microbiology and Immunology, University of North Carolina-Chapel Hill, Chapel Hill, NC; 9: Infection and Immunity Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Australia
  • Source: microbiolspec March 2019 vol. 7 no. 2 doi:10.1128/microbiolspec.GPP3-0061-2019
  • Received 13 February 2019 Accepted 22 February 2019 Published 29 March 2019
  • Jos A.G. van Strijp, [email protected]
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  • Abstract:

    has become a serious threat to human health. In addition to having increased antibiotic resistance, the bacterium is a master at adapting to its host by evading almost every facet of the immune system, the so-called immune evasion proteins. Many of these immune evasion proteins target neutrophils, the most important immune cells in clearing infections. The neutrophil attacks pathogens via a plethora of strategies. Therefore, it is no surprise that has evolved numerous immune evasion strategies at almost every level imaginable. In this review we discuss step by step the aspects of neutrophil-mediated killing of , such as neutrophil activation, migration to the site of infection, bacterial opsonization, phagocytosis, and subsequent neutrophil-mediated killing. After each section we discuss how evasion molecules are able to resist the neutrophil attack of these different steps. To date, around 40 immune evasion molecules of are known, but its repertoire is still expanding due to the discovery of new evasion proteins and the addition of new functions to already identified evasion proteins. Interestingly, because the different parts of neutrophil attack are redundant, the evasion molecules display redundant functions as well. Knowing how and with which proteins is evading the immune system is important in understanding the pathophysiology of this pathogen. This knowledge is crucial for the development of therapeutic approaches that aim to clear staphylococcal infections.

  • Citation: de Jong N, van Kessel K, van Strijp J. 2019. Immune Evasion by . Microbiol Spectrum 7(2):GPP3-0061-2019. doi:10.1128/microbiolspec.GPP3-0061-2019.


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has become a serious threat to human health. In addition to having increased antibiotic resistance, the bacterium is a master at adapting to its host by evading almost every facet of the immune system, the so-called immune evasion proteins. Many of these immune evasion proteins target neutrophils, the most important immune cells in clearing infections. The neutrophil attacks pathogens via a plethora of strategies. Therefore, it is no surprise that has evolved numerous immune evasion strategies at almost every level imaginable. In this review we discuss step by step the aspects of neutrophil-mediated killing of , such as neutrophil activation, migration to the site of infection, bacterial opsonization, phagocytosis, and subsequent neutrophil-mediated killing. After each section we discuss how evasion molecules are able to resist the neutrophil attack of these different steps. To date, around 40 immune evasion molecules of are known, but its repertoire is still expanding due to the discovery of new evasion proteins and the addition of new functions to already identified evasion proteins. Interestingly, because the different parts of neutrophil attack are redundant, the evasion molecules display redundant functions as well. Knowing how and with which proteins is evading the immune system is important in understanding the pathophysiology of this pathogen. This knowledge is crucial for the development of therapeutic approaches that aim to clear staphylococcal infections.

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Image of FIGURE 1

Evading neutrophil extravasation to the infection site. Mechanisms by which evades the steps in neutrophil extravasation. Neutrophils start to roll on the activated endothelium, which leads to firm adhesion and subsequently to transmigration through the endothelium. Red boxes indicate staphylococcal proteins, and blue boxes indicate host proteins. Abbreviations: PSGL-1, P-selectin glycoprotein 1; SSL, staphylococcal superantigen-like protein; ICAM-1, intracellular adhesion molecule 1; Eap, extracellular adherence protein; SElX, staphylococcal enterotoxin-like X. The figure was adapted from Servier Medical Art.

Source: microbiolspec March 2019 vol. 7 no. 2 doi:10.1128/microbiolspec.GPP3-0061-2019
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Image of FIGURE 2

Schematic overview of how evades priming, chemotaxis, and activation of neutrophils. Red boxes indicate staphylococcal proteins, and proteins shown in blue indicate host proteins. Abbreviations: TLR, Toll-like receptor; CXCR, chemokine receptor; ScpA, staphopain A; SSL, staphylococcal superantigen-like protein; FPR, formyl peptide receptor; FLIPr, FPR2 inhibitory protein; C5aR, C5a receptor; CHIPS, chemotaxis inhibitory protein of ; MMP, matrix metalloproteinase. The figure was adapted from Servier Medical Art.

Source: microbiolspec March 2019 vol. 7 no. 2 doi:10.1128/microbiolspec.GPP3-0061-2019
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Image of FIGURE 3

Diagram of the main pathways and components of the human complement system 3a and a schematic representation of evading opsonization and phagocytic uptake by neutrophil 3b. Red boxes indicate staphylococcal proteins, and blue boxes indicate host proteins. Abbreviations: IgG, immunoglobulin G; SpA, staphylococcal protein A; Sbi, staphylococcal binding of IgG; SCIN, staphylococcal complement inhibitor; SAK, staphylokinase; Aur, aureolysin; SSL, staphylococcal superantigen-like protein; Efb, extracellular fibrinogen-binding protein; Ecb, extracellular complement-binding protein. The figure was adapted from Servier Medical Art.

Source: microbiolspec March 2019 vol. 7 no. 2 doi:10.1128/microbiolspec.GPP3-0061-2019
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Image of FIGURE 4

Overview of evasion proteins that are involved in evading neutrophil killing. Enlargement of the phagosome is shown on the right. Red boxes indicate staphylococcal proteins, and blue boxes indicate host proteins. Staphyloxanthin provides a protective shield, KatA neutralizes hydrogen peroxide (HO) into water (HO) and oxygen (O), and SPIN inhibits MPO activity. MprF and the Dlt operon lead to an increase in positive charge of the bacterial surface. Abbreviations: SOD, superoxide dismutase; SAK, staphylokinase; KatA, catalase; MPO, myeloperoxidase; SPIN, staphylococcal peroxidase inhibitor; Aur, aureolysin; Hmp, flavohemoglobin; Ldh, -lactate dehydrogenase; Eap, extracellular adherence protein; EapH, extracellular adherence protein homologue; PR3, proteinase 3; CG, cathepsin G; NE, neutrophil elastase. The figure was adapted from Servier Medical Art.

Source: microbiolspec March 2019 vol. 7 no. 2 doi:10.1128/microbiolspec.GPP3-0061-2019
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Image of FIGURE 5

Evasion by staphylococcal toxins. Various leukocidins bind specific GPCRs, after which they form a pore and lyse host cells. PSMs are released inside the phagosome and can bind via FPR2. SAgs cross-link major histocompatibility complex class II and T-cell receptors. Abbreviations: GPCR, G-protein-coupled receptor; FPR, formyl protein receptor; PSMs, phenol-soluble modulins; Hla, hemolysin-alpha; SAgs, superantigens; MHC II, major histocompatibility complex II; TCR, T-cell receptor. The figure was adapted from Servier Medical Art.

Source: microbiolspec March 2019 vol. 7 no. 2 doi:10.1128/microbiolspec.GPP3-0061-2019
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Abbreviations of staphylococcal immune evasion proteins, what they evade, and on which MGE or paralogous gene cluster they are located

Source: microbiolspec March 2019 vol. 7 no. 2 doi:10.1128/microbiolspec.GPP3-0061-2019

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