John MacMicking PhD
Associate Professor of Microbial Pathogenesis
Cell-autonomous immunity; Constitutive and inducible host defense programs; Inflammasomes; Interferons (IFNs); Intracellular pathogens; Single cell analyses; Vertebrate and bacterial genetics
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 pathways which constitute the cell-autonomous defense network in mammals. Many of these genes including a new superfamily of immune GTPases are transcriptionally elicited via activating stimuli such as interferons (IFNs) and Toll-like receptor (TLR) signalling. The overall goal is to understand how individual cells protect themselves against major human bacterial pathogens like Mycobacterium tuberculosis and Salmonella serovars 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 coherent way? Answering these questions should help define the basic principles underlying this unique form of host resistance in complex, multicellular organisms.