John MacMicking, PhD
Research & Publications
Our laboratory focuses on the biological question of how all nucleated cells - irrespective of tissue origin - protect themselves against infection. This broad-based system of non-classical host defense is called cell-autonomous immunity and has recently been studied in plants but remains poorly understood in higher vertebrates. We are interested in characterizing the antimicrobial genes and circuitry which constitute the cell-autonomous defense network in mammals and their evolutionary inheritance from earlier prokaryotic and non-mammalian defense systems that encompass plants. Many of these genes including a new superfamily of immune GTPases are transcriptionally elicited via activating stimuli such as interferon (IFN) signalling. The overall goal is to understand how individual cells protect themselves against major human pathogens in vitro and in vivo. Some of the questions we are interested in are the following: What are the protein machineries and signaling hubs involved in restricting intracellular pathogens? Do such pathways operate in the cytosol or on specialized organelles, and is this response tailored to the subcellular lifestyle of the invading pathogen? Are common sets of host effectors shared across all diploid cells, or are there cell type-specific systems deployed in diverse histogenetic lineages and tissues? Lastly, can we reconstruct a virtual cell that assembles these host effector proteins and pathways in a computationally coherent way? Answering these questions should help define the basic principles underlying this unique form of host resistance in complex, multicellular organisms.
Specialized Terms: Cell-autonomous immunity; Evolution of host defense programs; Interferons (IFNs); Vertebrate, invertebrate and microbial genetics
Cell Biology; Immunity, Innate; Interferons; Computational Biology; Inflammasomes
- Rewiring the logic board of IFN signalingMacMicking J. Rewiring the logic board of IFN signaling Science Signaling 2022, 15: eadf0778. PMID: 36512642, DOI: 10.1126/scisignal.adf0778.
- Increasing the resilience of plant immunity to a warming climateKim JH, Castroverde CDM, Huang S, Li C, Hilleary R, Seroka A, Sohrabi R, Medina-Yerena D, Huot B, Wang J, Nomura K, Marr SK, Wildermuth MC, Chen T, MacMicking JD, He SY. Increasing the resilience of plant immunity to a warming climate Nature 2022, 607: 339-344. PMID: 35768511, PMCID: PMC9279160, DOI: 10.1038/s41586-022-04902-y.
- A human apolipoprotein L with detergent-like activity kills intracellular pathogensGaudet RG, Zhu S, Halder A, Kim BH, Bradfield CJ, Huang S, Xu D, Mamiñska A, Nguyen TN, Lazarou M, Karatekin E, Gupta K, MacMicking JD. A human apolipoprotein L with detergent-like activity kills intracellular pathogens Science 2021, 373 PMID: 34437126, PMCID: PMC8422858, DOI: 10.1126/science.abf8113.
- A phase-separated nuclear GBPL circuit controls immunity in plantsHuang S, Zhu S, Kumar P, MacMicking JD. A phase-separated nuclear GBPL circuit controls immunity in plants Nature 2021, 594: 424-429. PMID: 34040255, PMCID: PMC8478157, DOI: 10.1038/s41586-021-03572-6.
- Guanylate-binding proteins convert cytosolic bacteria into caspase-4 signaling platformsWandel MP, Kim BH, Park ES, Boyle KB, Nayak K, Lagrange B, Herod A, Henry T, Zilbauer M, Rohde J, MacMicking JD, Randow F. Guanylate-binding proteins convert cytosolic bacteria into caspase-4 signaling platforms Nature Immunology 2020, 21: 880-891. PMID: 32541830, PMCID: PMC7381384, DOI: 10.1038/s41590-020-0697-2.
- Cell-autonomous immunity by IFN-induced GBPs in animals and plantsHuang S, Meng Q, Maminska A, MacMicking JD. Cell-autonomous immunity by IFN-induced GBPs in animals and plants Current Opinion In Immunology 2019, 60: 71-80. PMID: 31176142, PMCID: PMC6800610, DOI: 10.1016/j.coi.2019.04.017.
- Bacteria disarm host-defence proteinsMacMicking JD. Bacteria disarm host-defence proteins Nature 2017, 551: 303-304. PMID: 29072295, DOI: 10.1038/nature24157.
- Interferon-induced guanylate-binding proteins in inflammasome activation and host defenseKim BH, Chee JD, Bradfield CJ, Park ES, Kumar P, MacMicking JD. Interferon-induced guanylate-binding proteins in inflammasome activation and host defense Nature Immunology 2016, 17: 481-489. PMID: 27092805, PMCID: PMC4961213, DOI: 10.1038/ni.3440.
- Cellular Self-Defense: How Cell-Autonomous Immunity Protects Against PathogensRandow F, MacMicking JD, James LC. Cellular Self-Defense: How Cell-Autonomous Immunity Protects Against Pathogens Science 2013, 340: 701-706. PMID: 23661752, PMCID: PMC3863583, DOI: 10.1126/science.1233028.
- IFN-Inducible GTPases in Host Cell DefenseKim BH, Shenoy AR, Kumar P, Bradfield CJ, MacMicking JD. IFN-Inducible GTPases in Host Cell Defense Cell Host & Microbe 2012, 12: 432-444. PMID: 23084913, PMCID: PMC3490204, DOI: 10.1016/j.chom.2012.09.007.
- Interferon-inducible effector mechanisms in cell-autonomous immunityMacMicking JD. Interferon-inducible effector mechanisms in cell-autonomous immunity Nature Reviews Immunology 2012, 12: 367-382. PMID: 22531325, PMCID: PMC4150610, DOI: 10.1038/nri3210.
- GBP5 Promotes NLRP3 Inflammasome Assembly and Immunity in MammalsShenoy AR, Wellington DA, Kumar P, Kassa H, Booth CJ, Cresswell P, MacMicking JD. GBP5 Promotes NLRP3 Inflammasome Assembly and Immunity in Mammals Science 2012, 336: 481-485. PMID: 22461501, DOI: 10.1126/science.1217141.
- A Family of IFN-γ–Inducible 65-kD GTPases Protects Against Bacterial InfectionKim BH, Shenoy AR, Kumar P, Das R, Tiwari S, MacMicking JD. A Family of IFN-γ–Inducible 65-kD GTPases Protects Against Bacterial Infection Science 2011, 332: 717-721. PMID: 21551061, DOI: 10.1126/science.1201711.
- Targeting of the GTPase Irgm1 to the phagosomal membrane via PtdIns(3,4)P2 and PtdIns(3,4,5)P3 promotes immunity to mycobacteriaTiwari S, Choi HP, Matsuzawa T, Pypaert M, MacMicking JD. Targeting of the GTPase Irgm1 to the phagosomal membrane via PtdIns(3,4)P2 and PtdIns(3,4,5)P3 promotes immunity to mycobacteria Nature Immunology 2009, 10: 907-917. PMID: 19620982, PMCID: PMC2715447, DOI: 10.1038/ni.1759.
- Immune Control of Tuberculosis by IFN-γ-Inducible LRG-47MacMicking JD, Taylor GA, McKinney JD. Immune Control of Tuberculosis by IFN-γ-Inducible LRG-47 Science 2003, 302: 654-659. PMID: 14576437, DOI: 10.1126/science.1088063.
- Identification of nitric oxide synthase as a protective locus against tuberculosisMacMicking J, North R, LaCourse R, Mudgett J, Shah S, Nathan C. Identification of nitric oxide synthase as a protective locus against tuberculosis Proceedings Of The National Academy Of Sciences Of The United States Of America 1997, 94: 5243-5248. PMID: 9144222, PMCID: PMC24663, DOI: 10.1073/pnas.94.10.5243.
- NITRIC OXIDE AND MACROPHAGE FUNCTIONMacMicking J, Xie Q, Nathan C. NITRIC OXIDE AND MACROPHAGE FUNCTION Annual Review Of Immunology 1997, 15: 323-350. PMID: 9143691, DOI: 10.1146/annurev.immunol.15.1.323.
- Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthaseMacMicking J, Nathan C, Hom G, Chartrain N, Fletcher D, Trumbauer M, Stevens K, Xie Q, Sokol K, Hutchinson N, Chen H, Mudget J. Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase Cell 1995, 81: 641-650. PMID: 7538909, DOI: 10.1016/0092-8674(95)90085-3.
- Inhibition of Viral Replication by Interferon-γ-Induced Nitric Oxide SynthaseKarupiah G, Xie Q, Buller R, Nathan C, Duarte C, MacMicking J. Inhibition of Viral Replication by Interferon-γ-Induced Nitric Oxide Synthase Science 1993, 261: 1445-1448. PMID: 7690156, DOI: 10.1126/science.7690156.