Dennis L. Stevens, Ph.D., M.D.

Summary: My longstanding research interest is the role of extracellular toxins in the pathogenesis of severe necrotizing infections and toxic shock syndromes caused by organisms such as group A streptococcus (the “flesh-eating disease”), Clostridium perfringens (gas gangrene) and Staphylococcus aureus (the “superbug”).  My laboratory utilizes in vitro and in vivo models to study the role of toxins in pathogenesis and host response and to develop novel diagnostics, vaccines and treatments to lessen the incidence and severity of these devastating infections.  As a practicing Infectious Disease physician at the VA Medical Center, I bring a unique clinical perspective and translational emphasis to all projects under my direction.  Indeed, our basic science research has provided the basis for the current treatment recommendations for these severe, toxin-mediated soft tissue infections.  I have a long history of training and mentoring students and biomedical researchers at all levels and I welcome WWAMI and INBRE students into my laboratory for unique research opportunities.

Minimum classes: Basic microbiology is required; biochemistry, immunology and/or prokaryotic genetics are recommended.

Projects: My ongoing projects include 1) the mechanisms of toxin-induced cardiac dysfunction in Streptococcal Toxic Shock Syndrome and 2) the mechanisms of antibiotic-induced bacterial toxin production.

The first project stems from our clinical observation that a unique form of cardiomyopathy develops in a subset of patients with group A streptococcal toxic shock syndrome (Strep TSS).  This cardiac dysfunction is characterized by severe biventricular dilatation and a striking reduction in ventricular performance. Patients are hypotensive and often receive often vasopressors to improve blood pressure.  However vessel constriction combined with failing heart performance results in reduced perfusion of the extremities leading to symmetrical gangrene the often requires amputation. In seeking the mechanisms responsible, we have shown that cardiomyocytes themselves area principal source of pro-inflammatory cytokines and of mediators that boost macrophages production of cardio-depressant factors. We have also demonstrated that pore-forming toxin streptolysin O directly disrupts cardiomyocyte contractility by dysregulating calcium signaling. Understanding the role of these cardiomyocyte-derived effectors and toxin-induced calcium intoxication in Strep TSS-associated cardiomyopathy may suggest new targets for therapeutic intervention.  Students could participate in studies using recombinant toxins and isolated cardiac cells to investigate the signaling events that mediate these deleterious changes in cardiac cell structure and function.

In the necrotizing soft tissue infections we study, elaboration of bacterial toxins mediate disease and curtailment or neutralization of toxin production is now recognized as an important clinical goal.  Our lab has previously published that many antibiotics, especially when at sub-inhibitory concentrations, actually increase and prolong bacterial toxin production.  This has important clinical implications for these life-threatening, toxin-mediated infections.  However, the signaling mechanisms responsible are entirely unknown though we believe them to be part of a common SOS stress-response pathway that is triggered upon perturbation of the bacterial cell wall and/or membrane.  Students participating in this project would use classical biochemical and genetic approaches to unravel the sequence of events leading to antibiotic-induced increases in virulence factor (toxin) production.