Despite the dramatic progress of 20th century medicine in fighting bacterial infections (including discovery of antibiotics and development of vaccines), infectious diseases caused by bacterial pathogens (e.g. tuberculosis, typhoid fever, pertussis, leprosy, bacterial meningitis and pneumonia) are still a serious public health problem (
http://www.who.int/epidemic_diseases/meningitis/en/(opens in new window);
http://www.who.int/mediacentre/factsheets/fs331/en/(opens in new window); WHO report, 2014). This is due to several factors that include the emergence of antibiotic resistance in bacteria, the difficulty of vaccinating extensive parts of populations in poor areas of the world, and our limited understanding of critical pathogenic mechanisms exploited by many of these bacterial pathogens during infection. Remarkably, how bacterial pathogens are cleared from the infected organism is still an uncertain and controversial issue. Indeed, despite extensive analyses of the recognition and signalling events that lead to pathogen identification and phagocytosis (Reddick and Alto, 2014), the mechanisms that result in killing or inhibition of the bacterial growth once the pathogen is taken up by a phagocytic immune cell are still not clearly understood. One of the major objectives of this proposal is to elucidate mechanisms of pathogen killing by immune cells and in particular will focus on the human pathogen Salmonella Typhi (S. Typhi).
Professor Spanò described a novel trafficking pathway that underlies S. Typhi host-restriction. A unique pathogenic feature of S. Typhi is its ability to infect only humans. The mechanisms of S. Typhi human restriction were completely unknown until recently, when she reported that a host trafficking pathway operating in macrophages contributes to prevent S. Typhi infection in mice (Spanò and Galan, 2012). Using a powerful combination of cell biology, genetic and mass spectrometry analyses, she showed that S. Typhi infection is restricted by a host trafficking pathway dependent on the small GTPase Rab32 and Biogenesis of Lysosome-related Organelles Complex (BLOC)-3 (Spanò and Galán, 2012; Fig. 1). Building on these findings this project will address the following questions:
1) What killing molecules does the Rab32-dependent trafficking pathway deliver to the S. Typhi vacuole?
2) How is the Rab32-dependent trafficking pathway regulated?
3) Is the Rab32-dependent trafficking pathway active in human macrophages? If so, how does S. Typhi evade killing to replicate in human macrophages?
