Abstract
In an environment full of potential pathogens it is of importance for organisms to mount a fast and effective defence. Antimicrobial peptides are ancient and integral effector molecules of the innate immune system. They are found in all kinds of species from bacteria to plants and animals, indicating their importance during evolution. They possess a broad-spectrum antimicrobial activity and some peptides can also participate in wound healing and connect the innate and adaptive immune systems.
Results presented in this thesis show that structural motifs connected with heparin-binding may confer antimicrobial activity to a given peptide. Peptides from various heparin-binding endogenous proteins exerted antimicrobial activity against Gram-positive and Gram-negative bacteria and similar results were obtained with consensus sequences for heparin-binding. Furthermore, we demonstrated that replacement of lysine and arginine by histidine in the consensus motifs abrogated the antibacterial effects of these peptides. Antibacterial effects of the histidine-rich consensus peptides were restored by the addition of Zn2+ or low pH. Similar results were obtained with histidine-rich peptides derived from domain 5 of kininogen and histidine-rich glycoprotein (HRGP).
HRGP, an abundant heparin-binding plasma protein, exerted antimicrobial effects against Gram-positive and Gram-negative bacteria and fungi. The antibacterial activity of HRGP was dependent on Zn2+-ions or low pH, and the antifungal activity was increased under low pH conditions.
Electron microscopy demonstrated that HRGP induced lysis of bacteria and fungi. Truncated HRGP, devoid of the heparin-binding and histidine-rich domain, was not antimicrobial. In addition, HRGP was found to have antifungal effects ex vivo when bound to fibrin clots.
Results presented in this thesis show that structural motifs connected with heparin-binding may confer antimicrobial activity to a given peptide. Peptides from various heparin-binding endogenous proteins exerted antimicrobial activity against Gram-positive and Gram-negative bacteria and similar results were obtained with consensus sequences for heparin-binding. Furthermore, we demonstrated that replacement of lysine and arginine by histidine in the consensus motifs abrogated the antibacterial effects of these peptides. Antibacterial effects of the histidine-rich consensus peptides were restored by the addition of Zn2+ or low pH. Similar results were obtained with histidine-rich peptides derived from domain 5 of kininogen and histidine-rich glycoprotein (HRGP).
HRGP, an abundant heparin-binding plasma protein, exerted antimicrobial effects against Gram-positive and Gram-negative bacteria and fungi. The antibacterial activity of HRGP was dependent on Zn2+-ions or low pH, and the antifungal activity was increased under low pH conditions.
Electron microscopy demonstrated that HRGP induced lysis of bacteria and fungi. Truncated HRGP, devoid of the heparin-binding and histidine-rich domain, was not antimicrobial. In addition, HRGP was found to have antifungal effects ex vivo when bound to fibrin clots.
| Original language | English |
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| Qualification | Doctor |
| Awarding Institution |
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| Supervisors/Advisors |
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| Award date | 2007 May 11 |
| Publisher | |
| ISBN (Print) | 978-91-85559-46-6 |
| Publication status | Published - 2007 |
Bibliographical note
Defence detailsDate: 2007-05-11
Time: 09:00
Place: GK-salen, Biomedicinskt centrum, Sölvegatan 19
External reviewer(s)
Name: Agerberth, Birgitta
Title: docent
Affiliation: Inst. för medicinsk biokemi och biofysik, Avdelningen för kemi, Karolinska Institutet
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<div class="article_info">E Andersson, V Rydengård, A Sonesson, M Mörgelin, L Björck and A Schmidtchen. <span class="article_issue_date">2004</span>. <span class="article_title">Antimicrobial activities of heparin-binding peptides.</span> <span class="journal_series_title">Eur J Biochem</span>, <span class="journal_volume">vol 271</span> <span class="journal_pages">pp 1219-26</span>.</div>
<div class="article_info">V Rydengård, E Andersson Nordahl and A Schmidtchen. <span class="article_issue_date">2006</span>. <span class="article_title">Zinc potentiates the antibacterial effects of histidine-rich peptides against Enterococcus faecalis</span> <span class="journal_series_title">FEBS J.</span>, <span class="journal_volume">vol 273</span> <span class="journal_pages">pp 2399-406</span>.</div>
<div class="article_info">L Kacprzyk, V Rydengård, M Malmsten and A Schmidtchen. <span class="article_issue_date"></span>. <span class="article_title">Antimicrobial activity of histidine-rich peptides is dependent of acidic conditions</span> (manuscript)</div>
<div class="article_info">V Rydengård, A-K Olsson, M Mörgelin and A Schmidtchen. <span class="article_issue_date">2007</span>. <span class="article_title">Histidine-rich glycoprotein exerts antibacterial activity</span> <span class="journal_series_title">FEBS J.</span>, <span class="journal_volume">vol 274</span> <span class="journal_pages">pp 377-89</span>.</div>
<div class="article_info">V Rydengård, L Kacprzyk, A-K Olsson, M Mörgelin, M Malmsten and A Schmidtchen. <span class="article_issue_date"></span>. <span class="article_title">Antifungal activity of histidine-rich glycoprotein</span> (manuscript)</div>
Subject classification (UKÄ)
- Dermatology and Venereal Diseases
Free keywords
- Dermatologi
- venereologi
- venereology
- Dermatology
- histidine-rich glycoprotein
- heparin-binding
- zinc
- low pH
- Medicine (human and vertebrates)
- Medicin (människa och djur)
- innate immunity
- antimicrobial
