University of Pennsylvania
School of Veterinary Medicine
3800 Spruce St., 390EE
Philadelphia, PA 19104
Our research focuses on the interplay of bacterial virulence mechanisms and host innate immune recognition strategies. In particular, we are interested in understanding how bacterial pathogens are detected by host cells as well as strategies utilized by bacterial pathogens to evade innate immune recognition.
Bacterial pathogens utilize specialized virulence-associated secretion systems or pore-forming toxins to deliver bacterial proteins into host cells. These proteins typically function to disrupt or modulate critical cellular processes in order to enable successful bacterial colonization of host niches. Two broad types of innate immune recognition exist to detect bacteria – pattern recognition, which detects conserved microbial structures present in all microbes of a given class, and detection of microbial virulence activities, triggered by microbial disruption of host cell processes or membranes. Macrophages infected with a variety of unrelated bacterial pathogens, but not avirulent or non-pathogenic bacteria, undergo a pro-inflammatory form of cell death termed pyroptosis, which depends on the cellular protease Caspase-1. Caspase-1 plays an important role in the cleavage and secretion of the pro-inflammatory cytokines IL-1ß and IL-18 and is therefore important in immune defense against various microbial infections. Members of the Nod-like receptor (NLR) family of cytosolic signaling proteins are responsible for recruiting Caspase-1 into multi-protein activating platforms termed ‘inflammasomes’. Inflammasome complexes are activated in response to a variety of bacterial, viral, and fungal infections and inflammasome activation plays an important role in host defense. However, successful pathogens have also evolved mechanisms to evade or subvert inflammasome activation, thereby avoiding caspase-1 dependent immune responses.
We use the Gram-negative bacterial pathogens Yersinia pseudotuberculosis and Salmonella Typhimurium in combination with genetic, biochemical, and imunological approaches on both the bacterial and host side to understand the bacterial signals that trigger inflammasome activation, how inflammasome activation is coupled to innate and adaptive immune responses, and how bacterial pathogens evade inflammasome-dependent immune responses.
Current projects in our lab address the following questions in host-pathogen interactions:
1. How does the inflammasome system sense conserved features of bacterial pathogens?
2. What are the mechanisms that enable pathogens to evade inflammasome activation?
3. How is inflammasome activation couple to other innate immune signaling pathways?
Current Brodsky Lab Members:
Post-doctoral Fellow: Meghan Wynosky-Dolfi
Graduate Student (MVP): Erin Zwack
Graduate Student (IGG): Naomi Philip
Research Specialist: Annelise Snyder