Abstract
Protein C inhibitor (PCI) is a heparin-binding serine proteinase inhibitor belonging to the family of serpin proteins. Here we describe that PCI exerts broad antimicrobial activity against bacterial pathogens. This ability is mediated by the interaction of PCI with lipid membranes, which subsequently leads to their permeabilization. As shown by negative staining electron microscopy, treatment of Escherichia coli or Streptococcus pyogenes bacteria with PCI triggers membrane disruption followed by the efflux of bacterial cytosolic contents and bacterial killing. The antimicrobial activity of PCI is located to the heparin-binding site of the protein and a peptide spanning this region was found to mimic the antimicrobial activity of PCI, without causing lysis or membrane destruction of eukaryotic cells. Finally, we show that platelets can assemble PCI on their surface upon activation. As platelets are recruited to the site of a bacterial infection, these results may explain our finding that PCI levels are increased in tissue biopsies from patients suffering from necrotizing fasciitis caused by S. pyogenes. Taken together, our data describe a new function for PCI in innate immunity.
Highlights
Our early response to an invading pathogen relies to a major part on our innate immune system
Antimicrobial effect of SEK20 Previous work has shown that SEK20, a peptide derived from Protein C inhibitor (PCI)
Antimicrobial peptides and proteins partake in this fight due to their ability to perforate the bacterial cell wall, which eventually will cause the efflux of bacterial cytosolic content and efficient bacterial killing
Summary
Our early response to an invading pathogen relies to a major part on our innate immune system. Pattern recognition proteins have two major tasks. Like tolllike receptors, evoke an inflammatory response, such as the induction of proinflammatory cytokines [2], while others are involved in the direct killing of the pathogen. There are scavenger receptors that can act as phagocytic receptors mediating direct non-opsonic uptake of pathogenic microbes and/ or their products [3]. There are pattern recognition proteins, such as complement, and antimicrobial peptides that fall into both categories. The anaphylatoxin peptide C3a is a potent chemoattractant for phagocytes, and has a direct antimicrobial effect [4]; other examples include chemotactic chemokines and neuropeptides [5,6]. The mode of the antimicrobial action of these substances is often based on their ability to penetrate the cell wall of the pathogen, which eventually leads to membrane disruption followed by cytosolic leakage and to the death of the targeted organism
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