| Popis: |
Iron is crucial for many cellular processes including DNA synthesis and respiration. The majority of iron in mammals is in heme within hemoproteins, inside cells, or transported through circulation by the glycoprotein transferrin, which constitutes the greatest iron source in serum. Limiting iron availability is an important facet of nutritional immunity to help prevent infection. Staphylococcus lugdunensis is a human skin commensal and opportunistic pathogen capable of causing a variety of infections, including particularly aggressive endocarditis. It is an emerging pathogen with elevated virulence compared to other species of coagulase-negative staphylococci. The versatility of S. lugdunensis to infect multiple niches and cause aggressive infection indicates that it likely adapts its cellular physiology to overcome host defenses, including iron limitation. In chapter 2, we demonstrate that, contrary to other staphylococci, S. lugdunensis does not produce a siderophore – small (kDa) iron-chelating molecules that strip iron from host glycoproteins, including transferrin, and deliver it to microorganisms. As such, serum is growth-inhibitory to S. lugdunensis, unless it is supplemented with an iron source. We have identified and characterized several iron-compound transport processes through inactivation of genes required for acquisition of each respective compound. S. lugdunensis transports the staphylococcal carboxylate siderophores staphyloferrin A and staphyloferrin B through Hts and Sir, respectively, and is able to directly appropriate siderophores produced by S. aureus when in coculture, to support its growth. Heme and hemoglobin-iron is acquired via Isd. In chapter 3, we demonstrate that hemolysis enhances growth in blood, in an Isd-dependent manner. An iron-regulated ATPase, FhuC, is required for import of several carboxylate and hydroxamate siderophores, whereas Sst1 transports catecholamine stress hormone-iron (ie. adrenaline, noradrenaline, dopamine). fhuC and sst1 mutants are impaired for growth in absence of hydroxamates and catecholamines, indicating additional substrates acquired by these are vital to S. lugdunensis. Using a novel systemic model of S. lugdunensis infection, we show that a isd fhuC sst mutant is significantly impaired in its ability to colonize internal murine organs, and cause sickness. We have detailed several iron-acquisition systems in S. lugdunensis and are first to show specific transporters are important for pathogenesis in the host. |
