Eric P. Skaar
Pathogenesis of Staphylococcus aureus and Bacillus anthracis infections
Staphylococcus aureus is a Gram-positive bacterium that colonizes the skin and anterior nares of approximately 25% of the human population. To initiate disease, the organism breaches the initial site of colonization and accesses deeper body tissues. If this occurs, S. aureus can infect virtually any body site. S. aureus is extremely virulent, causing 2% of clinical disease in all patient admissions. This bacterium is the most prevalent pathogen isolated from skin and soft tissue infection, is one of the four leading causes of food-borne illness, and is the second leading cause of infectious endocarditis in the United States.
In order to successfully cause disease, bacterial pathogens must acquire nutrients inside their hosts. The only nutrient thought to be limiting to the growth of bacteria inside of humans is iron. Iron sequestration inside the host is one of the most important first lines of defense against bacterial pathogens, a process known as "nutritional immunity." This iron "keep-away" is mediated primarily through the production of host iron-binding proteins. The most abundant of these iron-binding proteins are those that use heme as a cofactor, or hemoproteins. Our laboratory studies how Gram-positive bacteria steal iron from hemoproteins during infection.
We have identified a heme transport system known as the iron-regulated surface determinant system (isd) that is conserved in numerous Gram-positive pathogens including Staphylococcus aureus (Staph infections) and Bacillus anthracis (Anthrax). The Isd system encodes a molecular transport system responsible for recognizing human hemoglobin, transporting heme through the bacterial cell wall and membrane, and degrading heme in the cytoplasm to release free iron. Current research is focused on further understanding Isd-mediated heme transport and degradation in these important human pathogens.
We have recently created a technique that allows us to identify which nutrient-iron sources are preferred by bacteria during infection. This technique is based on utilizing nutrient samples that are exclusively labeled with minor stable isotopes of iron, and tracking these samples with sensitive mass spectrometry techniques as they move through the metabolic pathways of the cell. Stable isotope tracking has revealed that S. aureus preferentially imports heme-iron over other iron sources. In addition, stable isotope tracking identified a second system responsible for heme acquisition in S. aureus, which we call the heme transport system (hts). Inactivation of the hts system revealed a requirement for heme acquisition in staphylococcal pathogenesis. The creation of a stable isotope tracking technique allows us to answer previously unanswerable questions about bacterial nutrient acquisition during infection.
Our long term goals are to define the nutrient acquisition capabilities of Gram-positive pathogens in the hopes of identifying novel antimicrobial targets against organisms that are quickly becoming resistant to all existing therapies.