Novel host defence mechanisms during bacterial infections

Abstract: The immune system has evolved through thousands of years and its architecture has challenged the medical field since the first hieroglyphs and will likely continue do so. With our co-evolution with millions of other species, the complexity to treat infectious diseases has been a race in increasing speed ever since. The establishment of penicillin shortened the length of that battle against a broad spectrum of bacteria. Till this day, penicillin and other types of antibiotics have saved an enormous number of lives. Unfortunately, pathogenic bacteria don’t cease to develop. Many share similarities, which may be an advantage in attempts to cure infection. In other aspects- some bacteria, partly due to their very sophisticated biology develop resistance. This is one of several reasons that antibiotic resistance is one of the largest threats to survival of mankind today. Chronic wounds and pulmonary diseases are examples among many other conditions that have become difficult to treat by standard anti-biotic schemes. The need for novel, more specific, treatments for bacterial infections is urgent. Fortunately, the immune system carries a range of endogenous anti-bacterial proteins and peptides with many immunological features left to unravel. With a deeper understanding of their structure and function, these studies can hopefully aid in the search for alternatives to anti-biotics as well as bridge understanding between infection and other disease mechanisms. This thesis provides novel mechanistic insights to a group of endogenous proteins and their role during bacterial infections. Tissue Factor Pathway Inhibitor- 2, primarily known as a serine protease, highly expressed in placenta and additionally proposed to own function as a tumor- suppressor among others, was found to be important for survival during pulmonary P.aeruginosa infection in mice. Novel roles of complement components during persistent, intra-cellularly, infected skin by S.aureus was uncovered, a sophisticated mechanism facilitated by these bacteria to hide from the immune system. Lastly, plasma apoE was found anti-bacterial against E.coli and P.aeruginosa. Additionally, a mechanism on how apoE neutralize their endotoxins is suggested. Our findings suggest the role(s) for these host defence molecules to be re-considered, depending on site of expression as well as the bacteria they face.