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Bacterial Evasion of Host Antimicrobial Peptide Defenses

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  • Authors: Jason N. Cole1, Victor Nizet4
  • Editors: Indira T. Kudva7, Qijing Zhang8
  • VIEW AFFILIATIONS HIDE AFFILIATIONS
    Affiliations: 1: Department of Pediatrics, University of California San Diego, La Jolla, CA 92093; 2: School of Chemistry and Molecular Biosciences; 3: Australian Infectious Diseases Research Center, University of Queensland, St Lucia, Queensland 4072, Australia; 4: Department of Pediatrics, University of California San Diego, La Jolla, CA 92093; 5: Skaggs School of Pharmacy and Pharmaceutical Sciences; 6: Center for Immunity, Infection & Inflammation, University of California San Diego, La Jolla, CA 92093; 7: National Animal Disease Center, Agricultural Research Service, U.S. Department of Agriculture, Ames, IA; 8: Department of Veterinary Microbiology and Preventive Medicine, College of Veterinary Medicine, Iowa State University, Ames, IA
  • Source: microbiolspec January 2016 vol. 4 no. 1 doi:10.1128/microbiolspec.VMBF-0006-2015
  • Received 29 January 2015 Accepted 27 April 2015 Published 29 January 2016
  • Victor Nizet, vnizet@ucsd.edu
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  • Abstract:

    Antimicrobial peptides (AMPs), also known as host defense peptides, are small naturally occurring microbicidal molecules produced by the host innate immune response that function as a first line of defense to kill pathogenic microorganisms by inducing deleterious cell membrane damage. AMPs also possess signaling and chemoattractant activities and can modulate the innate immune response to enhance protective immunity or suppress inflammation. Human pathogens have evolved defense molecules and strategies to counter and survive the AMPs released by host immune cells such as neutrophils and macrophages. Here, we review the various mechanisms used by human bacterial pathogens to resist AMP-mediated killing, including surface charge modification, active efflux, alteration of membrane fluidity, inactivation by proteolytic digestion, and entrapment by surface proteins and polysaccharides. Enhanced understanding of AMP resistance at the molecular level may offer insight into the mechanisms of bacterial pathogenesis and augment the discovery of novel therapeutic targets and drug design for the treatment of recalcitrant multidrug-resistant bacterial infections.

    Abbreviations: ABC, adenosine triphosphate-binding cassette; AMPs, antimicrobial peptides; -Ara4N, 4-amino-4-deoxy--arabinose; GAC, group A carbohydrate; GAS, group A ; GBS, group B ; GlcNAc, -acetylglucosamine; HBD 1-6, human β-defensin 1-6; HD 5-6, human α-defensin 5-6; HNP 1-4, human neutrophil peptide 1-4; LL-37, human cathelicidin; LOS, lipooligosaccharide; LPS, lipopolysaccharide; LTA, lipoteichoic acid; mCRAMP, murine cathelicidin-related antimicrobial peptide; MprF, membrane protein multipeptide resistance factor; NETs, neutrophil extracellular traps; pEtN, phosphoethanolamine; PG, phosphatidylglycerol; Sap, sensitive to antimicrobial peptides ABC importer; SK, staphylokinase; TA, teichoic acid; TLR, toll-like receptor; WT, wild-type.

  • Citation: Cole J, Nizet V. 2016. Bacterial Evasion of Host Antimicrobial Peptide Defenses. Microbiol Spectrum 4(1):VMBF-0006-2015. doi:10.1128/microbiolspec.VMBF-0006-2015.

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/content/journal/microbiolspec/10.1128/microbiolspec.VMBF-0006-2015
2016-01-29
2017-06-26

Abstract:

Antimicrobial peptides (AMPs), also known as host defense peptides, are small naturally occurring microbicidal molecules produced by the host innate immune response that function as a first line of defense to kill pathogenic microorganisms by inducing deleterious cell membrane damage. AMPs also possess signaling and chemoattractant activities and can modulate the innate immune response to enhance protective immunity or suppress inflammation. Human pathogens have evolved defense molecules and strategies to counter and survive the AMPs released by host immune cells such as neutrophils and macrophages. Here, we review the various mechanisms used by human bacterial pathogens to resist AMP-mediated killing, including surface charge modification, active efflux, alteration of membrane fluidity, inactivation by proteolytic digestion, and entrapment by surface proteins and polysaccharides. Enhanced understanding of AMP resistance at the molecular level may offer insight into the mechanisms of bacterial pathogenesis and augment the discovery of novel therapeutic targets and drug design for the treatment of recalcitrant multidrug-resistant bacterial infections.

Abbreviations: ABC, adenosine triphosphate-binding cassette; AMPs, antimicrobial peptides; -Ara4N, 4-amino-4-deoxy--arabinose; GAC, group A carbohydrate; GAS, group A ; GBS, group B ; GlcNAc, -acetylglucosamine; HBD 1-6, human β-defensin 1-6; HD 5-6, human α-defensin 5-6; HNP 1-4, human neutrophil peptide 1-4; LL-37, human cathelicidin; LOS, lipooligosaccharide; LPS, lipopolysaccharide; LTA, lipoteichoic acid; mCRAMP, murine cathelicidin-related antimicrobial peptide; MprF, membrane protein multipeptide resistance factor; NETs, neutrophil extracellular traps; pEtN, phosphoethanolamine; PG, phosphatidylglycerol; Sap, sensitive to antimicrobial peptides ABC importer; SK, staphylokinase; TA, teichoic acid; TLR, toll-like receptor; WT, wild-type.

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FIGURE 1

Schematic representation of the multiple resistance mechanisms developed by bacteria to overcome host antimicrobial peptides. Modification of the bacterial outer membrane. Bacterial resistance to cationic antimicrobial peptides is mediated by alterations in surface charge. Gram-positive bacteria: -alanine modification of cell wall teichoic acid (), -lysine (), or -alanine modification of phosphatidylglycerol (). Gram-negative bacteria: aminoarabinose or acylation modifications of lipid A in LPS (), or addition of ethanolamine to lipid A (). The increased positive charge on bacterial surface repels cationic AMPs. Shielding of the bacterial surface through the trapping and inactivation of AMPs in the extracellular milieu enhances resistance and pathogenicity. Surface-associated capsule traps AMP (e.g., operon), surface protein binds AMP (e.g., GAS M1 protein, GBS PilB pilus protein), secreted protein binds AMP (e.g., GAS SIC protein or staphylokinase), or bacterial proteases release host proteoglycans to block AMP (e.g., LasA). Membrane efflux pumps function by translocating the AMP out of the cell (e.g., spp. Mtr, Typhimurium Sap, QacA, and spp. VraFG). Degradation and inactivation of AMPs by bacterial proteases (e.g., GAS streptococcal pyrogenic exotoxin B protease, SepA, Typhimurium PgtE, aureolysin and V8 protease, elastase, and gelatinase). Bacterial exposure to AMPs upregulates the expression of AMP-resistance genes through global gene regulatory networks (e.g., Typhimurium and PhoPQ and PmrAB). Alteration of host processes by bacteria, including the downregulation of host AMP production (e.g., spp. transcriptional factor MxiE) or the upregulation and activation of host AMP-degrading proteases (e.g., ). Abbreviations: om, bacterial outer membrane; im, bacterial inner membrane.

Source: microbiolspec January 2016 vol. 4 no. 1 doi:10.1128/microbiolspec.VMBF-0006-2015
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TABLE 1

Human antimicrobial peptides and murine cathelicidin mCRAMP

Source: microbiolspec January 2016 vol. 4 no. 1 doi:10.1128/microbiolspec.VMBF-0006-2015
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TABLE 2

Bacterial antimicrobial peptide resistance mechanisms

Source: microbiolspec January 2016 vol. 4 no. 1 doi:10.1128/microbiolspec.VMBF-0006-2015

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