Host Defense Properties of Collagen VI. A novel concept in connective tissue innate immunity

Abstract: Rapid and powerful host defense mechanisms are essential in order to overcome harmful actions of pathogenic bacteria. Antimicrobial peptides (AMPs) and proteins are vital effector molecules of the fast-acting innate immune system and exist virtually in all living organisms. They exert a broad spectrum of natural antibiotic activity, but also play important immunomodulatory functions in the host. During the past few decades, host defense molecules have gained remarkable attention as alternative treatments for bacterial infections due to the growing bacterial resistance to current antibiotics.This thesis sheds light on an intriguing and novel aspect of innate immunity in the context of connective tissues, where collagen VI emerges as a host defense molecule. Collagen VI is an extracellular matrix protein that forms complex microfibrillar networks in most connective tissues. The best studied form of collagen VI is a heterotrimer comprised of three α-chains, α1(VI), α2(VI) and α3(VI), where the majority of these α-chains are flanked by globular domains that share homology with von Willebrand factor type A (VWA) domains. The results presented in this thesis demonstrates that tissue-purified collagen VI exhibits a broad spectrum of antibacterial activity against Gram-positive and Gram-negative bacteria by disrupting the bacterial membranes and causing leakage of intracellular components, which subsequently leads to cell death. Interestingly, the expression of collagen VI was upregulated in the airways of chronic obstructive pulmonary disease (COPD) patients compared to healthy individuals. Upon airway epithelial damage in COPD, we found that collagen VI is exposed and serves both as an adhesive substrate and an antibacterial barrier for a number of pulmonary pathogens. In order to gain deeper insight into the antimicrobial nature of the collagen VI molecule, we identified and characterized cationic sequence motifs in the VWA domains of the α3(VI)-chain. These peptides showed a significant antibacterial activity against Gram-positive and Gram-negative bacteria in vitro and in vivo. Furthermore, some of them also displayed wound healing and anti-endotoxic properties in vitro.In conclusion, these data reveal for the first time in detail how extracellular matrix proteins, such as collagen VI, provide host defense mechanisms against bacterial infections in connective tissues. These findings also suggest a novel role for collagen VI-derived peptides in innate immunity and provide templates for the development of peptide-based antibacterial therapies.