Targeting bacterial infections by using immunomodulatory host defence peptides and proteins

Sammanfattning: Bacterial infections and sepsis are amongst the leading causes of death worldwide. Sepsis is caused by an uncontrolled systemic host response towards an invading pathogen. Due to the engagement of various systems including cellmediated responses, the coagulation and complement cascades, treatment of sepsis remains challenging. This is reflected in mortality rates of about 50 % for patients with septic shock, despite improved health care and antibiotic usage. Endogenous host defence peptides (HDPs) are essential components of the innate defence against invading pathogens. They exert multiple biological functions, and apart from their antimicrobial effects they may modulate inflammation, coagulation, and chemotaxis. Due to increasing bacterial resistance and due to the complex nature of severe bacterial infections, HDPs are today considered valuable candidates in the development of novel treatments for infections. In papers I-III the ability of HDPs, derived either from the C-terminus of human thrombin (HVF18, GKY25) or human tissue factor pathway inhibitor 2 (EDC34), to modulate innate immune responses caused by bacteria or lipopolysaccharide (LPS), were investigated. Thrombin-derived peptides significantly blocked LPS-induced responses including tissue-factor driven coagulation in vitro and in vivo and thereby improved survival in experimental animal models of LPS-induced shock and Pseudomonas aeruginosa sepsis (Paper I). The data in Paper II, demonstrate that the inhibition of these pro-inflammatory responses by GKY25, is not solely dependent on extracellular LPS-scavenging, but involves interactions with macrophages and monocytes. The TFPI-2 peptide (EDC34) also significantly modulated the coagulation cascade in vitro and in vivo and efficiently killed bacteria by enhancing complementmediated killing. The combination of these functions lead to improved survival in experimental models of E. coli or Pseudomonas sepsis (Paper III). In conclusion, the discovered immunomodulatory properties of these HDPs clearly indicate their potential for the development of new treatments for bacterial infections. Finally, a novel role of the abundant plasma protein heparin cofactor II (HCII) in host defence was discovered. HCII belongs to the class of serine proteinase inhibitors (serpins) and specifically inhibits human thrombin. However, its precise physiological role remained enigmatic. Paper IV shows that cleavage of HCII by human neutrophil elastase induces a conformational change in the HCII molecule, thereby uncovering a previously unknown antibacterial function of HCII.