Edward A. Miao, MD, PhD

Edward A. Miao, MD, PhD

Associate Professor
6105 Marsico Hall
CB#7290
919-966-6773


Miao Lab

Research

We study 1) how the innate immune system differentiates between pathogenic and non-pathogenic bacteria, and 2) how programmed cell death is used as a defense against intracellular infection. We study a variety of bacterial pathogens that cause infection in the intestines, liver, as well as systemic infection (including Salmonella, Listeria, Burkholderia, and Chromobacterium).

 We examine the cytosolic inflammasome sensors that detect virulence traits. For example, we discovered that the NLRC4 canonical inflammasome activates caspase-1 when it detects the activity of bacterial type III secretion systems by monitoring the host cytosol for bacterial flagellin and T3SS apparatus proteins (Miao et al. Nat Immunol 2006, Miao et al. PNAS 2010). We also discovered that the caspase-11 noncanonical inflammasome detects cytosol invasive bacteria (Aachoui et al. Science 2013) by monitoring for the contamination of the cytosol by bacterial LPS (Hagar et al. Science 2013).

These two inflammasome pathways trigger a form of programmed cell death called pyroptosis. Although discovered in 1992, we were the first to demonstrate in vivo that pyroptosis defends against intracellular bacteria (Miao et al. Nat Immunol 2010). Not only does pyroptosis destroy the infected cell and thus eliminate the intracellular niche, but it also converts cells into pore-induced intracellular trap (PIT), which prevent dissemination and simultaneously attracts neutrophils, which efferocytose (eat) the PIT with the bacteria trapped inside (Jørgensen et al. J Exp Med 2016).

Our studies on pyroptosis have led us to consider programmed cell death more broadly as a defense against infection. Infectious diseases were the primary selective pressures that drove evolution of the immune system. We therefore propose that infectious diseases therefore also shaped the evolution of programmed cell death pathways including not only pyroptosis, but also apoptosis and necroptosis (Jørgensen et al. Nat Rev Immunol 2017). Therefore, we are assembling a powerful compendium of infectious agents that we will use as immunologic probes to study the function of programmed cell death in vivo. We discovered ubiquitous environmental pathogens that are eliminated by pyroptosis so efficiently that they never infect immunocompetent hosts (Maltez et al. Immunity 2015, Aachoui et al. Cell Host Microbe 2015). In contrast, bona fide pathogens typically evolved to evade pyroptosis, enabling them to cause disease in immunocompetent people. By comparing bona fide pathogens to environmental pathogens, we are elucidating the evolutionary importance of PCD as an immunologic defense.

One of these novel model organisms, Chromobacterium violaceum, is cleared from the macrophage niche by pyroptosis, but then replicates within hepatocytes. The hepatocyte niche is cleared when inflammasome-driven IL-18 primes natural killer (NK) cells to identify and attack the infected hepatocytes. Remarkably, although well known to attack viruses and cancer, this was the first example of NK cells using perforin-cytotoxicity to combat an intracellular bacterium (Maltez et al. Immunity 2015). This has led our lab to study how pyroptosis and NK cytotoxicity act as parallel programmed cell death mechanisms to defend against intracellular infection.

Ongoing projects consider how a variety of programmed cell death pathways defend against infection, but can also cause immunopathology when excessively activated.

School of Medicine profile and press release:

https://healthtalk.unchealthcare.org/the-battle-against-microscopic-bugs/

https://healthtalk.unchealthcare.org/unc-researchers-identify-molecule-that-triggers-septic-shock/

Complete Link to publications

2016    Pyroptosis triggers pore-induced intracellular traps (PITs) that caputre bacteria and lead to their clearance by efferocytosis     Jørgensen, I., Y. Zhang, B.A. Krantz, and E.A. Miao PMC5030797 J Exp Med

2015    Inflammasomes coordinate pyroptosis and NK cytotoxicity to clear infection by a ubiquitous environmental bacterium Maltez, V.I., A.L. Tubbs, K.D. Cook, Y. Aachoui, E.L. Falcone, S.M. Holland, J.K. Whitmire, and E.A. Miao PMC4654968         Immunity

2015    Canonical inflammasomes drive IFN-to prime caspase-11 in defense against a cytosol-invasive bacterium Aachoui, Y., Y. Kajiwara, I.A. Leaf, D. Mao, J.P.Y. Ting, J. Coers, A. Aderem, J.D. Buxbaum, and E.A. Miao PMC4567510   Cell Host and Microbe

2013    Cytoplasmic LPS activates caspase-11: implications in TLR4-independent endotoxic shock Hagar, J.A., D.A. Powel, Y. Aachoui, R.K. Ernst, and E.A. Miao PMC3931427  Science

2013    Caspase-11 protects against bacteria that escape the vacuole Aachoui, Y. *, I.A. Leaf*, J.A. Hagar*, M.F. Fontana, C.G. Campos, D.E. Zak, M.H. Tan, P.A. Cotter, R.E. Vance, A. Aderem, and E.A. Miao PMC3697099 *These authors contributed equally     Science

 2010    Caspase-1-induced pyroptosis is an innate immune effector mechanism against intracellular bacteria Miao, E.A., I.A. Leaf, P.M. Treuting, D.P. Mao, M. Dors, A. Sarkar, S.E. Warren, M.D. Wewers, and A. Aderem PMC3058225 Nat Immunol

 2010    Innate immune detection of the type III secretion apparatus through the NLRC4 inflammasome Miao, E.A., D.P. Mao, N. Yudkovsky, R. Bonneau, C.G. Lorang, S.E. Warren, I.A. Leaf, and A. Aderem PMC2840275  Proc Natl Acad Sci USA

2006    Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1 via Ipaf Miao, E.A., C.M. Alpuche-Aranda, M. Dors, A.E. Clark, M.W. Bader, S.I. Miller, and A. Aderem PMID: 16648853.   Nat Immunol

Selected Review Articles

2017    Gasdermins: Effectors of pyroptosis Kovacs, S.B. and E.A. Miao Review. In press Trends Cell Biology

2017    Programmed cell death as a defense against infection Jørgensen, I, M. Rayamajhi, and E.A. Miao Invited review. PMC5328506  Nat Rev Immunol

 

 

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