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John MacMicking, PhD

Associate Professor of Microbial Pathogenesis and of Immunobiology; Member, Yale Systems Biology Institute; Investigator, Howard Hughes Medical Institute

Contact Information

John MacMicking, PhD

Mailing Address

  • Howard Hughes Medical Institute, Yale Systems Biology Institute

    850 West Campus Drive, ISTC 341

    West Haven, CT 06516-7389

    United States

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Research Summary

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 inheritance from earlier prokaryotic and non-mammalian systems. 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

Coauthors

Research Interests

Cell Biology; Immunity, Innate; Interferons; Computational Biology; Inflammasomes

Research Image

The GBP coatomer: A new nanomachine built for antimicrobial defense

The human IFN-induced GTPase, GBP1, generates an immune “coatomer” comprising nearly 30,000 monomers on Salmonella typhimurium which serves as a recruitment platform for the inflammasome machinery and other innate immune signaling proteins.

Selected Publications

  • A human apolipoprotein L with detergent-like activity kills intracellular pathogens.Gaudet 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 (New York, N.Y.) 2021, 373 PMID: 34437126, PMCID: PMC8422858, DOI: 10.1126/science.abf8113.
  • A phase-separated nuclear GBPL circuit controls immunity in plants.Huang 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 platforms.Wandel 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 plants.Huang 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.
  • Microbiology: Bacteria disarm host-defence proteins.MacMicking JD. Microbiology: Bacteria disarm host-defence proteins. Nature 2017, 551: 303-305. PMID: 29072295, DOI: 10.1038/nature24157.
  • Interferon-induced guanylate-binding proteins in inflammasome activation and host defense.Kim 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: 481-9. PMID: 27092805, PMCID: PMC4961213, DOI: 10.1038/ni.3440.
  • Cellular self-defense: how cell-autonomous immunity protects against pathogens.Randow F, MacMicking JD, James LC. Cellular self-defense: how cell-autonomous immunity protects against pathogens. Science (New York, N.Y.) 2013, 340: 701-6. PMID: 23661752, PMCID: PMC3863583, DOI: 10.1126/science.1233028.
  • GBP5 promotes NLRP3 inflammasome assembly and immunity in mammals.Shenoy AR, Wellington DA, Kumar P, Kassa H, Booth CJ, Cresswell P, MacMicking JD. GBP5 promotes NLRP3 inflammasome assembly and immunity in mammals. Science (New York, N.Y.) 2012, 336: 481-5. PMID: 22461501, DOI: 10.1126/science.1217141.
  • Interferon-inducible effector mechanisms in cell-autonomous immunity.MacMicking JD. Interferon-inducible effector mechanisms in cell-autonomous immunity. Nature Reviews. Immunology 2012, 12: 367-82. PMID: 22531325, PMCID: PMC4150610, DOI: 10.1038/nri3210.
  • IFN-inducible GTPases in host cell defense.Kim BH, Shenoy AR, Kumar P, Bradfield CJ, MacMicking JD. IFN-inducible GTPases in host cell defense. Cell Host & Microbe 2012, 12: 432-44. PMID: 23084913, PMCID: PMC3490204, DOI: 10.1016/j.chom.2012.09.007.
  • A family of IFN-γ-inducible 65-kD GTPases protects against bacterial infection.Kim 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 (New York, N.Y.) 2011, 332: 717-21. PMID: 21551061, DOI: 10.1126/science.1201711.
  • Targeting of the GTPase Irgm1 to the phagosomal membrane via PtdIns(3,4)P(2) and PtdIns(3,4,5)P(3) promotes immunity to mycobacteria.Tiwari S, Choi HP, Matsuzawa T, Pypaert M, MacMicking JD. Targeting of the GTPase Irgm1 to the phagosomal membrane via PtdIns(3,4)P(2) and PtdIns(3,4,5)P(3) promotes immunity to mycobacteria. Nature Immunology 2009, 10: 907-17. PMID: 19620982, PMCID: PMC2715447, DOI: 10.1038/ni.1759.
  • Immune control of tuberculosis by IFN-gamma-inducible LRG-47.MacMicking JD, Taylor GA, McKinney JD. Immune control of tuberculosis by IFN-gamma-inducible LRG-47. Science (New York, N.Y.) 2003, 302: 654-9. PMID: 14576437, DOI: 10.1126/science.1088063.
  • Nitric oxide and macrophage function.MacMicking J, Xie QW, Nathan C. Nitric oxide and macrophage function. Annual Review Of Immunology 1997, 15: 323-50. PMID: 9143691, DOI: 10.1146/annurev.immunol.15.1.323.
  • Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase.MacMicking JD, Nathan C, Hom G, Chartrain N, Fletcher DS, Trumbauer M, Stevens K, Xie QW, Sokol K, Hutchinson N. Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase. Cell 1995, 81: 641-50. PMID: 7538909.
  • Inhibition of viral replication by interferon-gamma-induced nitric oxide synthase.Karupiah G, Xie QW, Buller RM, Nathan C, Duarte C, MacMicking JD. Inhibition of viral replication by interferon-gamma-induced nitric oxide synthase. Science (New York, N.Y.) 1993, 261: 1445-8. PMID: 7690156.
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