Genetics, Microbial; Immunity, Cellular; Interferons; Mycobacterium tuberculosis; Salmonella; Toll-Like Receptors; Inflammasomes
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.
Specialized Terms: Cell-autonomous immunity; Constitutive and inducible host defense programs; Inflammasomes; Interferons (IFNs); Intracellular pathogens; Single cell analyses; Vertebrate and bacterial genetics
- Randow F., MacMicking, J.D., and James, L.C. Cellular self-defense: How cell-autonomous immunity protects against pathogens. Science. 340,701-706 (2013).
- Shenoy, A.R., Wellington, D.A., Kumar, P., Kassa, H., Booth, C.J., Cresswell, P., and MacMicking, J.D. GBP5 promotes NLRP3 inflammasome assembly and immunity in mammals. Science. 336, 481-485 (2012).
- MacMicking, J.D. IFN-induced effector mechanisms in cell-autonomous immunity. Nature Reviews of Immunology. 12, 367-382. (2012).
- Kim, B.H., Shenoy, A.R., Kumar, P., Bradfield, C.J., and MacMicking, J.D. IFN-inducible GTPases in host cell defense. Cell Host & Microbe. 12, 434-444 (2012).
- Kim, B.H., Shenoy, A.R., Kumar, P., Das, R., Tiwari, S., and MacMicking, J.D. A family of IFN-gamma-inducible 65kD GTPases protect against bacterial infection. Science. 332, 717-721 (2011).
- 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, H.P., Matsuzawa, T., Pypaert, M, and MacMicking, J.D. Nat Immunol. 2009 Aug;10(8):907-17. doi: 10.1038/ni.1759.
- MacMicking, J.D. Macrophage activation and host defense. Cell Host & Microbe. 5, 405-407 (2009).
- A role for lipid bodies in the cross-presentation of phagocytosed antigens by MHC class I in dendritic cells. Bougneres, L., Helft, J., Tiwari, S., Vargas, P., Chang, B.H.J., Chan, L., Campisi, L., Lauvau, G., Hugues, S., Kumar, P., Kamphorst, A.O., Lennonn Dumenil, A.M., Nussenzweig, M., MacMicking, J.D., Amigorina, S., and Guemonprez, P. Immunity. 2009 Aug 21;31(2):232-44. doi: 10.1016/j.immuni.2009.06.022.
- MacMicking, J.D. Immune control of phagosomal bacteria by p47 GTPases. Current. Opinion in Microbiology. 8,1-9 (2005).
- MacMicking, J.D. IFN-inducible GTPases and immunity to intracellular pathogens. Trends Immunology. 25, 601-609 (2004).
- MacMicking J.D., Taylor, G.A., and McKinney, J.D. Immune control of tuberculosis by IFN-gamma-inducible LRG-47. Science. 302, 654-659 (2003).
- Shiloh, M.U., MacMicking, J.D., Nicholson, S., Brause, J.E., Potter, S., Marino, M., Fang, F., Dinauer, M.C. and Nathan, C.F. Phenotype of mice and macrophages deficient in both phagocyte oxidase and inducible oxide synthase. Immunity. 10, 29-38 (1999).
- Diefenbach, A., Schindler, H., Donhauser, N., Lorenz, E., Laskay, T., MacMicking, J., Rollinghoff, M., Gresser, I., and Bogdan. C. Regulation of the innate immune response to Leishmania by type I interferon (IFN-a/ß) and by type 2 nitric oxide synthase.
- MacMicking, J.D., North, R.J., LaCourse, R., Mudgett, J.S., Shah, S.K., and Nathan, C.F. Identification of nitric oxide synthase as a protective locus against tuberculosis. Proceedings of the National Academy of Science USA. 94, 5243-5248 (1997).
- MacMicking, J.D., Nathan, C., Hom, G., Chartrain, N., Trumbauer, M., Stevens, K., Xie, Q.w., Sokol, K., Fletcher, D.S., Hutchinson, N., Chen, H., and Mudgett, J.S. Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase. Cell. 81, 641-650 (1995).
- Karupiah, G., Xie, Q.w., Buller, R.M.L., Nathan, C., Duarte, C., and MacMicking, J.D. Inhibition of viral replication by interferon-gamma-induced nitric oxide synthase. Science. 261:1445-1448 (1993).