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Thrombin-derived C-terminal peptide reduces Candida-induced inflammation and infection in vitro and in vivo

Dahlman, Anna LU ; Puthia, Manoj LU ; Petrlova, Jitka LU ; Schmidtchen, Artur LU and Petruk, Ganna LU orcid (2021) In Antimicrobial Agents and Chemotherapy 65(11).
Abstract

Infections due to the opportunistic fungus Candida have been on the rise in the last decades, especially in immunocompromised individuals and hospital settings. Unfortunately, the treatments available today are limited. Thrombin-derived C-terminal peptide (TCP-25) is an antimicrobial peptide (AMP) with antibacterial and immunomodulatory effects. In this work, we, for the first time, demonstrate the ability of TCP-25 ability to counteract Candida in vitro and in vivo. Using a combination of viable count assay (VCA), radial diffusion assay (RDA), and fluorescence and transmission electron microscopy analyses, TCP-25 was found to exert a direct fungicidal activity. An inhibitory activity of TCP-25 on NF-kB activation induced by both... (More)

Infections due to the opportunistic fungus Candida have been on the rise in the last decades, especially in immunocompromised individuals and hospital settings. Unfortunately, the treatments available today are limited. Thrombin-derived C-terminal peptide (TCP-25) is an antimicrobial peptide (AMP) with antibacterial and immunomodulatory effects. In this work, we, for the first time, demonstrate the ability of TCP-25 ability to counteract Candida in vitro and in vivo. Using a combination of viable count assay (VCA), radial diffusion assay (RDA), and fluorescence and transmission electron microscopy analyses, TCP-25 was found to exert a direct fungicidal activity. An inhibitory activity of TCP-25 on NF-kB activation induced by both zymosan alone and heat-killed C. albicans was demonstrated in vitro using THP-1 cells, and in vivo using NF-kB reporter mice. Moreover, the immunomodulatory property of TCP-25 was further substantiated in vitro by analyzing cytokine responses in human blood stimulated with zymosan, and in vivo employing a zymosan-induced peritonitis model in C57BL/6 mice. The therapeutic potential of TCP-25 was demonstrated in mice infected with luminescent C. albicans. Finally, the binding between TCP-25 and zymosan was investigated using circular dichroism spectroscopy and intrinsic fluorescence analysis. Taken together, our results show that TCP-25 has a dual function by inhibiting Candida as well as the associated zymosan-induced inflammation. The latter function is accompanied by a change in secondary structure upon binding to zymosan. TCP-25, therefore, shows promise as a novel drug candidate against Candida infections.

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author
; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Antifungal, Antifungal agent, Antimicrobial peptide, Candida, Thrombin, Zymosan
in
Antimicrobial Agents and Chemotherapy
volume
65
issue
11
article number
e01032-21
publisher
American Society for Microbiology
external identifiers
  • pmid:34424043
  • scopus:85117453580
ISSN
0066-4804
DOI
10.1128/AAC.01032-21
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2021 Dahlman et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
id
18c8f618-cd0e-4ec4-9167-658ee17faa71
date added to LUP
2021-11-22 09:18:44
date last changed
2025-01-12 18:28:12
@article{18c8f618-cd0e-4ec4-9167-658ee17faa71,
  abstract     = {{<p>Infections due to the opportunistic fungus Candida have been on the rise in the last decades, especially in immunocompromised individuals and hospital settings. Unfortunately, the treatments available today are limited. Thrombin-derived C-terminal peptide (TCP-25) is an antimicrobial peptide (AMP) with antibacterial and immunomodulatory effects. In this work, we, for the first time, demonstrate the ability of TCP-25 ability to counteract Candida in vitro and in vivo. Using a combination of viable count assay (VCA), radial diffusion assay (RDA), and fluorescence and transmission electron microscopy analyses, TCP-25 was found to exert a direct fungicidal activity. An inhibitory activity of TCP-25 on NF-kB activation induced by both zymosan alone and heat-killed C. albicans was demonstrated in vitro using THP-1 cells, and in vivo using NF-kB reporter mice. Moreover, the immunomodulatory property of TCP-25 was further substantiated in vitro by analyzing cytokine responses in human blood stimulated with zymosan, and in vivo employing a zymosan-induced peritonitis model in C57BL/6 mice. The therapeutic potential of TCP-25 was demonstrated in mice infected with luminescent C. albicans. Finally, the binding between TCP-25 and zymosan was investigated using circular dichroism spectroscopy and intrinsic fluorescence analysis. Taken together, our results show that TCP-25 has a dual function by inhibiting Candida as well as the associated zymosan-induced inflammation. The latter function is accompanied by a change in secondary structure upon binding to zymosan. TCP-25, therefore, shows promise as a novel drug candidate against Candida infections.</p>}},
  author       = {{Dahlman, Anna and Puthia, Manoj and Petrlova, Jitka and Schmidtchen, Artur and Petruk, Ganna}},
  issn         = {{0066-4804}},
  keywords     = {{Antifungal; Antifungal agent; Antimicrobial peptide; Candida; Thrombin; Zymosan}},
  language     = {{eng}},
  number       = {{11}},
  publisher    = {{American Society for Microbiology}},
  series       = {{Antimicrobial Agents and Chemotherapy}},
  title        = {{Thrombin-derived C-terminal peptide reduces Candida-induced inflammation and infection in vitro and in vivo}},
  url          = {{http://dx.doi.org/10.1128/AAC.01032-21}},
  doi          = {{10.1128/AAC.01032-21}},
  volume       = {{65}},
  year         = {{2021}},
}