The Brodsky lab focuses on the interplay of bacterial virulence mechanisms and host innate immune recognition strategies. We are interested in how bacterial pathogens are sensed by host cells, how this sensing contributes to antimicrobial immune defense, and how bacterial pathogens evade innate immune recognition.
The immune system utilizes two types of recognition strategies to detect microbes – membrane-bound pattern recognition receptors (PRRs), such as Toll-like Receptors, detect conserved microbial structures present in all microbes of a given class. Cytosolic sensors, consisting primarily of the NLR family, detect microbial virulence activities that result from the disruption of cellular processes or the inappropriate contamination of the host cell cytosol by microbial products. The Brodsky lab is investigating a family of proteases known as caspases, which regulate cell death in response to various environmental stimuli including cellular stress and infection. Caspase-1 and caspase-8 in particular play important roles in the activation of cell death and secretion of pro-inflammatory cytokines in response to microbial infection. Both caspase-1 and caspase-8 can be recruited to different multi-protein activating platforms where they can be activated to induce downstream cell death and inflammatory responses. We seek to understand how both the caspase-8 and caspase-1 platforms are activated during inflammatory or infectious conditions, and how this activation is regulated by both cellular and microbial factors.
Indeed, successful pathogens have evolved mechanisms to evade or subvert cell death pathways, thereby avoiding caspase-1 and caspase-8-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.
Recent studies in our laboratory have revealed unexpected links between caspase-1 activation and activation of other cell death pathways (Philip et al., PNAS 2014; Peterson et al, J.Immunol 2016; Peterson et al, J.Exp.Med. 2017), and have identified a novel mechanism for sensing of TCA cycle metabolites by the NLRP3 inflammasome pathway (Wynosky-Dolfi et al., J Exp Med, 2014). Further studies have also demonstrated that bacterial pathogens tune the delivery of specific virulence factors into the host cell, so as to avoid triggering inflammasome response pathways (Zwack et al., MBio 2015; Zwack et al., Infect. Immun 2017)
Ongoing Projects in the Brodsky Lab involve (1) Dissecting the role of extrinsic cell death pathway components in inflammation. (2) Defining the contribution of inflammasome activation to anti-Salmonella immunity. (3) Determining the role of cell death in anti-bacterial immunity in vivo (4) Understanding the role of bacterial secretion system pore proteins in inflammasome activation
Current Brodsky Lab Members:
Meghan Wynosky-Dolfi (Senior Research Scientist)
Elisabet Bjanes (Graduate Student - MVP)
Alexandra Delaney (Graduate Student - MVP)
Daniel Sorobetea (Post-doctoral fellow)
Daniel Grubaugh (Post-doctoral fellow)
Baofeng Hu (Lab Manager)
Former Lab Members:
Erin Zwack (Graduate Student - MVP; current - Post-doc, Victor Torres Lab, NYU)
Naomi Philip (Graduate Student - IGG; current - Post-doc, Ruslan Medzhitov Lab, Yale)
Lance Peterson (Graduate Student - IGG; current - Pediatrics Resident, Washington University)
Annelise Snyder (Technician; current - PhD Student, UW Immunology)
Marta Andres-Terre (Undergrad; current - PhD Student, Denise Monack Lab, Stanford University)
Dorothy Tovar (SUIP student; current - PhD Student, Stanford University Microbiology&Immunology)
Lindsay Theodore (Summer student; current - PhD Student, Harvard University BBS program)
AB (Molecular Biology) Princeton University, 1997PhD (Microbiology&Immunology) Stanford University, 2004