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Daniel Fisch Lab
Innate Immune Cell Biology
Daniel Fisch Lab
Innate Immune Cell Biology
Our group investigates how the innate immune system detects danger, processes information, and executes protective responses. We are interested in the molecular “machines” that allow cells to sense infection and translate these signals into inflammation, antimicrobial defense, and communication with the adaptive immune system. By uncovering how these systems work at the molecular level, we aim to better understand immunity in health and disease, with implications for infection, autoimmunity, and cancer.
Our lab uses genetics, cell biology, biochemistry and quantitative imaging to uncover the principles that govern innate immune cell biology. By studying the detectors, computers, and executors of immunity as integrated molecular machines, we seek to build a mechanistic framework for how immune responses are initiated, computed, and controlled and how they can be manipulated for therapeutic benefit.
Toll-like Receptor Signaling – Detectors and Computers of Immune Responses
Our research focuses on how innate immune cells (e.g. macrophages) process danger signals through Toll-like receptors (TLRs). These receptors act as “detectors” for microbial and damage-associated molecules and initiate inflammatory signaling programs that instruct the broader immune response. Rather than signaling through simple linear pathways, TLRs assemble large, dynamic protein platforms (e.g. Myddosomes) that function as molecular “computers,” integrating inputs and generating specific outputs.
We investigate how these signaling complexes assemble at endogenous levels inside cells, how their composition and structure change over time, and how these properties determine the quality and magnitude of inflammation. We are also developing synthetic tools that allow us to build and control these signaling machines on demand. By dissecting how TLR signaling is organized at the molecular level, we aim to uncover principles that explain how distinct immune responses are computed and how they might be selectively tuned.
Guanylate-Binding Proteins (GBPs) – Guarding the Cell from Within
Another focus of our research is understanding how cells detect and eliminate intracellular pathogens. We study a family of interferon-inducible proteins known as Guanylate-binding proteins (GBPs), which function at the frontline of cell-intrinsic immunity. GBPs can directly sense microbial invasion, target pathogens that enter the cytosol, and trigger inflammatory defense programs, including forms of programmed cell death to eliminate infected cells. In this way, they act as both detectors and executors of immune defense.
Beyond classical pattern-recognition systems, GBPs participate in “guard” mechanisms that monitor the integrity of key cellular processes and respond when pathogens disrupt them. This strategy provides flexibility: rather than recognizing only conserved microbial molecules, guard pathways detect the consequences of infection itself. Our work seeks to define how GBPs are activated, how their activity is carefully restrained to prevent damage to healthy tissue, and how these regulatory circuits shape inflammation. We are particularly interested in whether manipulating GBP pathways could enhance antimicrobial immunity or cancer immunotherapy.
Fisch D, Ohri V, Anastasakou E, Wesemann LJ, Choi JH, Lindblad KE, Kagan JC. TRAM promotes Toll-like-receptor-free myddosome signal transduction. Nature. 2026 Sep 23;. doi: 10.1038/s41586-026-11052-y. [Epub ahead of print] PubMed PMID: 42778610.
Fisch D, Zhang T, Sun H, Ma W, Tan Y, Gygi SP, Higgins DE, Kagan JC. Molecular definition of the endogenous Toll-like receptor signalling pathways. Nature. 2024 Jul;631(8021):635-644. doi: 10.1038/s41586-024-07614-7. Epub 2024 Jul 3. PubMed PMID: 38961291; PubMed Central PMCID: PMC12925374.
Fisch D, Pfleiderer MM, Anastasakou E, Mackie GM, Wendt F, Liu X, Clough B, Lara-Reyna S, Encheva V, Snijders AP, Bando H, Yamamoto M, Beggs AD, Mercer J, Shenoy AR, Wollscheid B, Maslowski KM, Galej WP, Frickel EM. PIM1 controls GBP1 activity to limit self-damage and to guard against pathogen infection. Science. 2023 Oct 6;382(6666):eadg2253. doi: 10.1126/science.adg2253. Epub 2023 Oct 6. PubMed PMID: 37797010; PubMed Central PMCID: PMC7615196.
Fisch D, Clough B, Khan R, Healy L, Frickel EM. Toxoplasma-proximal and distal control by GBPs in human macrophages. Pathog Dis. 2022 Jan 7;79(9). doi: 10.1093/femspd/ftab058. PubMed PMID: 34931666; PubMed Central PMCID: PMC8752258.
Fisch D, Evans R, Clough B, Byrne SK, Channell WM, Dockterman J, Frickel EM. HRMAn 2.0: Next-generation artificial intelligence-driven analysis for broad host-pathogen interactions. Cell Microbiol. 2021 Jul;23(7):e13349. doi: 10.1111/cmi.13349. Epub 2021 May 16. PubMed PMID: 33930228.
Fisch D, Clough B, Domart MC, Encheva V, Bando H, Snijders AP, Collinson LM, Yamamoto M, Shenoy AR, Frickel EM. Human GBP1 Differentially Targets Salmonella and Toxoplasma to License Recognition of Microbial Ligands and Caspase-Mediated Death. Cell Rep. 2020 Aug 11;32(6):108008. doi: 10.1016/j.celrep.2020.108008. PubMed PMID: 32783936; PubMed Central PMCID: PMC7435695.
Fisch D, Bando H, Clough B, Hornung V, Yamamoto M, Shenoy AR, Frickel EM. Human GBP1 is a microbe-specific gatekeeper of macrophage apoptosis and pyroptosis. EMBO J. 2019 Jul 1;38(13):e100926. doi: 10.15252/embj.2018100926. Epub 2019 Jun 3. PubMed PMID: 31268602; PubMed Central PMCID: PMC6600649.
Fisch D, Yakimovich A, Clough B, Wright J, Bunyan M, Howell M, Mercer J, Frickel E. Defining host-pathogen interactions employing an artificial intelligence workflow. Elife. 2019 Feb 12;8. doi: 10.7554/eLife.40560. PubMed PMID: 30744806; PubMed Central PMCID: PMC6372283.
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