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John MacMicking, PhD

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 defense is called cell-autonomous innate immunity and has recently been studied in bacteria and plants but still remains poorly understood in humans. We are interested in characterizing the antimicrobial genes and circuitry which constitute the human cell-autonomous defense network and its evolutionary inheritance from earlier prokaryotic and eukaryotic defense systems. Many of these genes are elicited via activating stimuli such as interferon (IFN) signalling as part of an elaborate defense program sometimes referred to as the "interferome". An overall goal is to understand how the interferome protects us against major human pathogens at both the nanoscale and macroscale levels. 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 sub-cellular lifestyle of the invading pathogen? Are common sets of IFN-induced 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, with implications for tackling some of world's most important infectious diseases. Specialized Terms: Cell-autonomous innate immunity; Host defense; Interferons (IFNs); Viruses, Bacteria, Cryo-electron tomography

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Research Interests

Cell Biology; Immunity, Innate; Interferons; Host-Pathogen Interactions

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The GBP1 defense complex: A new nanomachine built for IFN-induced immunity to infection

The human IFN-induced GTPase, GBP1, generates a massive immune defense complex comprising nearly 30,000 conformers on Salmonella typhimurium which serves as a recruitment platform for the inflammasome machinery and other innate immune signaling proteins.

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