Igor E. Brodsky
· PhDVerifiedUniversity of Pennsylvania · Infection and Immunity
Active 1995–2025
About
Igor E. Brodsky, PhD, is a Professor of Microbiology in the Department of Microbiology at the University of Pennsylvania's Perelman School of Medicine. His research focuses on the interplay of bacterial virulence mechanisms and host innate immune recognition strategies. His lab investigates how bacterial pathogens are sensed by host cells, how this sensing contributes to antimicrobial immune defense, and how bacterial pathogens evade innate immune recognition. Brodsky's work emphasizes the immune system's recognition strategies, including membrane-bound pattern recognition receptors such as Toll-like Receptors and cytosolic sensors primarily from the NLR family. His research explores the regulation and activation of caspases, particularly caspase-1 and caspase-8, which are involved in cell death and secretion of pro-inflammatory cytokines during microbial infection. His lab uses bacterial pathogens like Yersinia pseudotuberculosis and Salmonella typhimurium, employing genetic, biochemical, and immunological approaches to understand inflammasome activation, immune responses, and bacterial evasion tactics. His contributions include revealing links between caspase-1 activation and other cell death pathways, identifying mechanisms for sensing TCA cycle metabolites via the NLRP3 inflammasome, and demonstrating how bacterial secretion systems modulate virulence factor delivery to avoid immune detection. Ongoing projects in his lab aim to dissect the roles of cell death pathways in inflammation, define inflammasome contributions to anti-Salmonella immunity, and understand bacterial strategies to evade immune responses.
Research topics
- Biology
- Immunology
- Cell biology
- Genetics
- Virology
- Chemistry
- Biochemistry
- Microbiology
Selected publications
bioRxiv (Cold Spring Harbor Laboratory) · 2025-02-26 · 2 citations
preprintOpen accessSenior authorCorrespondingAbstract Enteroinvasive bacterial pathogens are responsible for an enormous worldwide disease burden that critically affects the young and immunocompromised. Yersinia pseudotuberculosis is a Gram-negative enteric pathogen, closely related to the plague agent Y. pestis, that colonizes intestinal tissues, induces the formation of pyogranulomas along the intestinal tract, and disseminates to systemic organs following oral infection of experimental rodents. Prior studies proposed that systemic tissues were colonized by a pool of intestinal replicating bacteria distinct from populations within Peyer’s patches and mesenteric lymph nodes. Whether bacteria within intestinal pyogranulomas serve as the source for systemic dissemination, and the relationship between bacterial populations within different tissue sites is poorly defined. Moreover, the factors that regulate Yersinia colonization and dissemination are not well understood. Here, we demonstrate, using Sequence Tag-based Analysis of Microbial Populations in R (STAMPR), that remarkably small founder populations independently colonize intestinal and systemic tissues. Notably, intestinal pyogranulomas contain clonal populations of bacteria that are restricted and do not spread to other tissues. However, populations of Yersinia are shared among systemic organs and the blood, suggesting that systemic dissemination occurs via hematogenous spread. Finally, we demonstrate that TNF signaling is a key contributor to the bottlenecks limiting both tissue colonization and lymphatic dissemination of intestinal bacterial populations. Altogether, this study reveals previously undescribed aspects of infection dynamics of enteric bacterial pathogens. Importance Bacterial escape from the intestine can lead to severe disease, including sepsis, organ damage, and death. However, the intestinal bacterial population dynamics governing the colonization of mucosal and systemic tissues and the intestinal sites that seed systemic spread are not clear. Yersinia pseudotuberculosis is a rodent and human intestinal pathogen closely related to the plague agent and provides a natural rodent-adapted model to study systemic bacterial dissemination. Our findings define the infection dynamics of enteric Yersinia and the impact of the innate immune system on Yersinia colonization of the intestine and systemic organs.
Inflammasomes primarily restrict cytosolic Salmonella replication within human macrophages
eLife · 2025-03-27 · 1 citations
articleOpen accessSalmonella enterica serovar Typhimurium is a facultative intracellular pathogen that utilizes its type III secretion systems (T3SSs) to inject virulence factors into host cells and colonize the host. In turn, a subset of cytosolic immune receptors respond to T3SS ligands by forming multimeric signaling complexes called inflammasomes, which activate caspases that induce interleukin-1 (IL-1) family cytokine release and an inflammatory form of cell death called pyroptosis. Human macrophages mount a multifaceted inflammasome response to Salmonella infection that ultimately restricts intracellular bacterial replication. However, how inflammasomes restrict Salmonella replication remains unknown. We find that caspase-1 is essential for mediating inflammasome responses to Salmonella and restricting bacterial replication within human macrophages, with caspase-4 contributing as well. We also demonstrate that the downstream pore-forming protein gasdermin D (GSDMD) and Ninjurin-1 (NINJ1), a mediator of terminal cell lysis, play a role in controlling Salmonella replication in human macrophages. Notably, in the absence of inflammasome responses, we observed hyperreplication of Salmonella within the cytosol of infected cells as well as increased bacterial replication within vacuoles, suggesting that inflammasomes control Salmonella replication primarily within the cytosol and also within vacuoles. These findings reveal that inflammatory caspases and pyroptotic factors mediate inflammasome responses that restrict the subcellular localization of intracellular Salmonella replication within human macrophages.
ACS Bio & Med Chem Au · 2025-07-02 · 4 citations
articleOpen access= 1 μM). Even when specificities are shared, the caspases exhibit different efficiencies and potencies for shared substrates and inhibitors. Altogether, we report the development of new tools that will facilitate the study of caspases and their roles in biology.
bioRxiv (Cold Spring Harbor Laboratory) · 2025-09-11 · 1 citations
preprintOpen accessSenior authorCorrespondingAbstract Salmonella enterica comprises over 2500 serovars that are responsible for over 90 million annual infections and 100,000 deaths worldwide. Despite this diversity, our understanding of innate immune responses to Salmonella is based on extensive study of a few serovars, primarily Typhimurium, including strains that cannot replicate within primary murine macrophages. Non-replicating Salmonella trigger caspase-1 and −11-dependent pyroptosis. Whether the innate immune system distinguishes between replicating and non-replicating intracellular Salmonella is poorly defined. Here we demonstrate that replicating Salmonella enterica induce a distinct pathway of TNF- and caspase-8-driven apoptosis via host TLR4 and Salmonella Pathogenicity Island-2 activity. This pathway is independent of gasdermin D and involves the apoptotic pore protein Pannexin-1. Combined loss of Pannexin-1 and gasdermin D resulted in defective control of systemic Salmonella , indicating that these pathways function together to promote anti- Salmonella host defense. Altogether, our findings uncover a previously unappreciated pathway by which macrophages sense intracellular replicating bacteria.
bioRxiv (Cold Spring Harbor Laboratory) · 2025-02-27 · 1 citations
preprintOpen accessAbstract Caspases are a family of cysteine proteases that act as molecular scissors to cleave substrates and regulate biological processes such as programmed cell death and inflammation. Extensive efforts have been made to identify caspase substrates and to determine factors that dictate substrate specificity. We recently discovered that that the human inflammatory caspases (caspases-1, -4, and -5) cleave the cytokines IL-1β and IL-18 in a sequence-dependent manner. Here, we report the development of a new peptide-based probe and inhibitor based on the tetrapeptide sequence of IL-18 (LESD). We found that this inhibitor was most selective and potent at inhibiting caspase-8 activity (IC 50 = 50 nM). We also discovered that our LESD-based inhibitor is more potent than the currently used z-IETD-FMK inhibitor that is thought to be the most selective and potent inhibitor of caspase-8. Accordingly, we demonstrate that the LESD based inhibitor prevents caspase-8 activation during Yersinia pseudotuberculosis infection in primary bone-marrow derived macrophages. Furthermore, we characterize the selectivity and potency of currently known substrates and inhibitors for the apoptotic and inflammatory caspases using the same activity units of each caspase. Our findings reveal that VX-765, a known caspase-1 inhibitor, also inhibits caspase-8 (IC 50 = 1 µM) and even when specificities are shared, the caspases have different efficiencies and potencies for shared substrates and inhibitors. Altogether, we report the development of new tools that will facilitate the study of caspases and their roles in biology.
Nature Nanotechnology · 2025-08-11 · 42 citations
articleOpen accessbioRxiv (Cold Spring Harbor Laboratory) · 2025-12-23 · 1 citations
articleOpen accessAbstract The distal small intestine plays vital roles in host physiology by regulating nutrient and fluid homeostasis. Despite being impacted in Crohn’s disease and a major target for a range of infections, we know relatively little about the complexity of cellular responses and cell-cell communication in the ileum during infection. Single cell and spatial transcriptomics have emerged as powerful technologies to study tissue heterogeneity in the gut, but these tools have focused on the large intestine, in part due to the accessibility of this tissue for biopsies and its importance in cancer. Here we present GutPath, an atlas of over 500,000 single cells with RNA and protein expression profiles for 91 cell states in the ileum across diverse infectious archetypes. We show that GutPath accurately captures established immune responses to infection while revealing pathogen-specific responses in enterocytes. To highlight the discovery potential of this atlas, we identify a novel enterocyte cell state present during Yersinia pseudotuberculosis infection that is spatially linked to bacterial load and tissue pathology. GutPath establishes a much-needed resource for the immunology community that will accelerate the study of the transcriptional diversity of cellular landscapes in the small intestine.
2025-03-27
peer-reviewOpen accessmBio · 2025-09-09 · 6 citations
articleOpen accessSenior authorABSTRACT Enteroinvasive bacterial pathogens are responsible for an enormous worldwide disease burden that critically affects the young and immunocompromised. Yersinia pseudotuberculosis is a gram-negative enteric pathogen closely related to the plague agent Y. pestis that colonizes intestinal tissues, induces the formation of pyogranulomas along the intestinal tract, and disseminates to systemic organs following oral infection of experimental rodents. Prior studies proposed that systemic tissues were colonized by a pool of intestinal replicating bacteria distinct from populations within Peyer’s patches and mesenteric lymph nodes. Whether bacteria within intestinal pyogranulomas serve as the source for systemic dissemination and the relationship between bacterial populations within different tissue sites is poorly defined. Moreover, the host factors that regulate Yersinia colonization and dissemination are not well understood. Here, we demonstrate using sequence tag-based analysis of microbial populations in R (STAMPR) that remarkably small founder populations independently colonize intestinal and systemic tissues. Notably, intestinal pyogranulomas contain clonal populations of bacteria that are restricted and do not spread to other tissues. However, Yersinia populations are shared among systemic organs and the blood, suggesting that systemic dissemination occurs via hematogenous spread. Finally, we demonstrate that TNF signaling is a key contributor to the bottlenecks limiting both initial colonization and subsequent dissemination of orally acquired bacterial populations. Altogether, this study reveals previously undescribed aspects of infection dynamics of enteric bacterial pathogens. IMPORTANCE Dissemination of bacteria following intestinal infection can lead to severe disease, including sepsis, organ damage, and death. However, the intestinal bacterial population dynamics governing the colonization of mucosal and systemic tissues and the intestinal sites that seed systemic spread are not clear. Yersinia pseudotuberculosis is a rodent and human intestinal pathogen closely related to the plague agent and provides a natural rodent-adapted model to study systemic bacterial dissemination. Our findings define the infection dynamics of enteric Yersinia and the impact of the innate immune system on Yersinia colonization of the intestine and systemic organs.
Proceedings of the National Academy of Sciences · 2025-11-11 · 1 citations
articleOpen accessMetastatic outgrowth requires that cancer cells delaminate from the primary tumor, intravasate, survive in circulation, extravasate, migrate to, and proliferate at a distal site. Recurrent genetic drivers of metastasis remain elusive, suggesting that unlike the early steps of oncogenesis, metastasis drivers may be variable. We develop a framework for identifying metastasis regulators using CRISPR/Cas9-based screening in a genetically defined organoid model of colorectal adenocarcinoma. We conduct in vitro screens for invasion and migration alongside orthotopic, in vivo screens for gain of metastasis in a syngeneic mouse model. We identify CTNNA1 and BCL2L13 as bona fide metastasis-specific suppressors which do not confer any selective advantage in primary tumors. CTNNA1 loss promotes cell invasion and migration, and BCL2L13 loss promotes anchorage-independent survival and non-cell-autonomous changes to macrophage polarization. This study demonstrates proof of principle that large-scale genetic screening can be performed in tumor-organoid models in vivo and identifies novel regulators of metastasis.
Recent grants
NIH · $440k · 2016
Novel role of CARD19 in cell death and anti-bacterial host defense
NIH · $443k · 2018–2021
NIH · $143k · 2008
NIH · $449k · 2016
NIH · $1.7M · 2018
Frequent coauthors
- 35 shared
Sunny Shin
University of Pennsylvania
- 23 shared
Ruslan Medzhitov
Howard Hughes Medical Institute
- 20 shared
Meghan A. Wynosky-Dolfi
University of Pennsylvania
- 17 shared
Naomi H. Philip
Yale University
- 14 shared
Andy J. Minn
University of Pennsylvania
- 12 shared
Erin E. Zwack
New York University
- 12 shared
Richard A. Flavell
Howard Hughes Medical Institute
- 12 shared
James P. Grayczyk
University of Pennsylvania
Labs
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