Novel Aspects of the Coagulation System in Host Defence

Abstract: Bacterial infections are a major global threat to public health and sepsis is a major cause of morbidity and mortality. Sepsis incidence is rising, with supportive treatments and antibiotics being the main treatment possibilities. Sepsis is characterised by an excessive and uncontrolled immune and coagulation response, leading to tissue damage, capillary leakage, and multiple organ failure. Although sepsis treatment has improved over the last decades, it still remains a challenging disease because of the multiplicity of symptoms caused by bacteria and bacterial products and in parallel, increased bacterial resistance. Therefore, there is clearly a demand for novel therapeutic strategies for sepsis, and correspondingly, also a need for increased knowledge on host defence molecules and their actions. The major goal of this thesis was to identify and characterise novel endogenous host defence peptides (HDPs) and proteins, to define their antimicrobial and immunomodulatory effects, and to explore their potential as novel anti-infectives. In response to injury and wounding, activation of the coagulation system generates a fibrin clot that prevents excessive blood loss and provides a first protective physical barrier. During this process, various HDPs are formed which play a role in the prevention of infections. In this work, we have defined new host defence activities of proteolytically generated HDPs derived from several well-known plasma proteins involved in initiation or control of blood clotting, including the main coagulation factor thrombin, and the protease inhibitors tissue factor pathway inhibitor -1 and -2, as well as heparin cofactor II. The discovered HDPs were antibacterial against Gram-positive and Gram-negative bacteria as well as fungi. Furthermore, the HDPs also displayed other bioactive roles, including down-regulation of inflammatory responses (thrombin-derived peptide, truncated heparin cofactor II), modulation of coagulation (TFPI-2 peptide), and boosting of complement activation (TFPI-1 and -2 peptides). Moreover, in animal models of septic shock and bacterial sepsis, several of these multifunctional HDPs significantly decreased mortality. In conclusion, host defence peptides with multiple properties could be potentially interesting in the development of the next generation of therapeutics for the treatment of bacterial infections and sepsis.