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The contribution of cationic antimicrobial peptides to the host immune response to bacterial infection

University of British Columbia

Many species produce cationic antimicrobial peptides as components of their immune systems. To combat bacterial infections, the host immune response, or treatment regime, must aim to kill the invading pathogen and manage the inflammatory response to the bacteria and its released components. Certain cationic peptides, such as the human peptide, LL-37, can be produced in large quantities at sites of infection/inflammation and their expression can be further induced by bacterial products such as lipopolysaccharide (LPS) and pro-inflammatory cytokines such as tumor necrosis factor-cc (TNF-α). The primary focus of this research was to further define the contribution of cationic peptides to the immune response to bacterial infection. A greater understanding of the biological characteristics of these molecules will help in evaluating their therapeutic potential. Both synthetic and natural peptides were studied here, most notably a hybrid peptide of cecropin and melittin (CEMA) and the human peptide, LL-37.1 found that the cationic peptides had multifaceted activities including the ability to bind to lipoteichoic acid (LTA) and LPS and in the case of LPS, to interfere with its ability to bind LPS binding protein (LBP). The peptides were also found to be effective in neutralizing the host response to bacterial components from both Gram-negative and Gram-positive bacteria. I found that CEMA selectively inhibited macrophage gene expression in response to LPS stimulation. CEMA and LL-37 treatment of murine macrophages resulted in the up-regulation of at least 35 genes and downregulation of at least 21 genes. Macrophage genes affected by the peptides included those involved in chemotaxis. These changes were then confirmed at the protein level in both in vitro and in vivo situations. For example, CEMA and LL-37 induced the production of chemokines and up-regulated the surface expression of chemokine receptors. When given intratracheally to mice, LL-37 increased levels of the chemokine, monocyte chemoattractant protein-1 (MCP-1) but not the pro-inflammatory cytokine, TNF-α. Thus, this study indicated that synthetic as well as natural cationic peptides produced in response to bacterial infections could contribute to the immune response by limiting the damage caused by bacterial products and by recruiting immune cells to tissue sites harboring infectious agents.

Thesis/Dissertation

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2009-10-01

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http://hdl.handle.net/2429/13511

Microbiology and Immunology

University of British Columbia

UBCV

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