441 Bridgeside Point II
450 Technology Dr.
Pittsburgh, PA 15219
The Richardson Lab is primarily focused on the effects of immunometabolism on infectious disease outcomes. Immunometabolism encompasses the metabolic adaptations that a microbe must make to thrive in the face of an immune response as well as the metabolic adaptations that host cells undergo in order to mount an effective immune response. Specifically, we study immunometabolism in the context of infections caused by the Gram-positive pathogen Staphylococcus aureus. Regarding host metabolism, we are particularly interested in the roles of arginine during infection. Arginine is a semi-essential amino acid that serves two important purposes during inflammation: it is the substrate of Inducible Nitric Oxide Synthase (iNOS) for the production of nitric oxide (NO·) as well as being a substrate for Arginase-1 (Arg-1) that generates ornithine for the production of compounds known as polyamines. During a typical S. aureus skin infection, infiltrating immune cells initially express high levels of iNOS leading to robust NO· production. Eventually this inflammatory response yields to a pro-fibrotic response and a switch from iNOS to Arg-1 expression in local immune cells. These two phases of the host response exert different effects on S. aureus survival within the abscess. First, S. aureus is uniquely resistant to the effects of NO·, thus the initial inflammatory phase of the host response is ineffective at clearing the bacteria. In contrast, S. aureus is exquisitely sensitive to polyamines, which accumulate during the pro-fibrotic phase. Consequently, it is during this phase where the viable bacteria are cleared from the tissue. We are vigorously working to understand several aspects of these observations in an effort to improve treatment options against multi drug-resistant strains as well as to learn basic concepts about immunometabolism during infection.
NO·-resistance in S. aureus. S. aureus has evolved from a genus of commensal colonizers of mammalian skin to be one of the most significant human pathogens. This is in large part due to the horizontal acquisition of a myriad of virulence determinants. However, in parallel, S. aureus has also metabolically evolved to thrive in the face of the host immune response. For instance, S. aureus can grow in the presence of host NO· while other members of the staphylococci cannot. NO· normally exerts antibacterial activity by interfering with and constraining the metabolic capabilities of invading bacteria. S. aureushas evolved NO·-resistance through the acquisition of a number of genes encoding metabolic enzymes that allow the organism to adopt a metabolic state that is intrinsically resistant to NO·. We are trying to understand the nature of the S. aureus NO·-resistant metabolic state as it is critical for the pathogenicity of this bacterium.
Polyamine-sensitivity in S. aureus. Polyamines (e.g. spermine and spermidine) are said to be essential for all life and are highly abundant in active cells. We were the first to show that S. aureus lacks polyamine synthesis and that polyamines within healing wounds are highly toxic to this bacterium. In addition, we discovered that an emerging S. aureus clone currently dominating the clinical landscape has evolved polyamine-resistance, which has contributed to the remarkable success of this hypervirulent lineage. We are interested in the mechanism of polyamine toxicity towards S. aureus and if this trait can be exploited for treatment options.
Diabetes and S. aureus Infections. Diabetic patients suffer disproportionately from S. aureus infections with higher incidences and more frequent treatment failures. We became interested in this link when we learned that S. aureus NO·-resistant metabolism requires glucose, an overly abundant nutrient in diabetic patients. In addition to excess blood glucose affording NO·-resistance to S. aureus during infection, our studies pointed to other important aspects of diabetes that contribute to disease severity. Namely, diabetic wounds never shift from the inflammatory phase into the pro-fibrotic phase, which is so critical to clearing S. aureus skin infections. We have discovered links between insulin signaling and polyamine production that contribute to the metabolic priming of host phagocytes. We are interested in exploring this aspect of host immunometabolism and the inherent defect(s) in the diabetic immune response in an effort to develop treatments for this highly susceptible patient population.
Lance R. Thurlow, PhD; Research Assistant Professor
Elyse Paluscio, PhD; Postdoctoral Fellow