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      Inhibition of P2X Receptors Protects Human Monocytes against Damage by Leukotoxin from Aggregatibacter actinomycetemcomitans and α-Hemolysin from Escherichia coli

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          α-Hemolysin (HlyA) from Escherichia coli and leukotoxin A (LtxA) from Aggregatibacter actinomycetemcomitans are important virulence factors in ascending urinary tract infections and aggressive periodontitis, respectively. The extracellular signaling molecule ATP is released immediately after insertion of the toxins into plasma membranes and, via P2X receptors, is essential for the erythrocyte damage inflicted by these toxins. Moreover, ATP signaling is required for the ensuing recognition and phagocytosis of damaged erythrocytes by the monocytic cell line THP-1. Here, we investigate how these toxins affect THP-1 monocyte function. We demonstrate that both toxins trigger early ATP release and a following increase in the intracellular Ca 2+ concentration ([Ca 2+] i) in THP-1 monocytes. The HlyA- and LtxA-induced [Ca 2+] i response is diminished by the P2 receptor antagonist in a pattern that fits the functional P2 receptor expression in these cells. Both toxins are capable of lysing THP-1 cells, with LtxA being more aggressive. Either desensitization or blockage of P2X 1, P2X 4, or P2X 7 receptors markedly reduces toxin-induced cytolysis. This pattern is paralleled in freshly isolated human monocytes from healthy volunteers. Interestingly, only a minor fraction of the toxin-damaged THP-1 monocytes eventually lyse. P2X 7 receptor inhibition generally prevents cell damage, except from a distinct cell shrinkage that prevails in response to the toxins. Moreover, we find that preexposure to HlyA preserves the capacity of THP-1 monocytes to phagocytose damaged erythrocytes and may induce readiness to discriminate between damaged and healthy erythrocytes. These findings suggest a new pharmacological target for protecting monocytes during exposure to pore-forming cytolysins during infection or injury.

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          Author and article information

          Role: Editor
          Infect Immun
          Infect. Immun
          Infection and Immunity
          American Society for Microbiology (1752 N St., N.W., Washington, DC )
          15 August 2016
          17 October 2016
          November 2016
          : 84
          : 11
          : 3114-3130
          MEMBRANES, Department of Biomedicine, Aarhus University, Aarhus C, Denmark
          University of Illinois Urbana
          Author notes
          Address correspondence to Helle A. Praetorius, hp@ 123456biomed.au.dk .

          Citation Fagerberg SK, Jakobsen MR, Skals M, Praetorius HA. 2016. Inhibition of P2X receptors protects human monocytes against damage by leukotoxin from Aggregatibacter actinomycetemcomitans and α-hemolysin from Escherichia coli. Infect Immun 84:3114–3130. doi: 10.1128/IAI.00674-16.

          PMC5067745 PMC5067745 5067745 00674-16
          Copyright © 2016, American Society for Microbiology. All Rights Reserved.
          Page count
          Figures: 11, Tables: 0, Equations: 0, References: 83, Pages: 17, Words: 12282
          Funded by: Lundbeckfonden (Lundbeck Foundation) http://dx.doi.org/10.13039/501100003554
          Award ID: R100-A9482
          Award Recipient : Helle A. Praetorius
          Funded by: Det Frie Forskningsråd (DFF) http://dx.doi.org/10.13039/501100004836
          Award ID: DFF-1331-00203A
          Award Recipient : Helle A. Praetorius
          Funded by: Det Frie Forskningsråd (DFF) http://dx.doi.org/10.13039/501100004836
          Award ID: DFF-0602-02145B
          Award Recipient : Marianne Skals
          Cellular Microbiology: Pathogen-Host Cell Molecular Interactions


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