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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

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John MacMicking, PhD

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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 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

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Research Interests

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

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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.

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