Edward Miao, M.D./Ph.D.
Research
Our laboratory is interested in determining how the innate immune system differentiates between pathogenic and non-pathogenic bacteria. We examine the pattern recognition receptors involved in detecting virulence factors, and the resulting immune response. Research focuses on the cytosolic detectors that form inflammasomes, activating Caspase-1. Caspase-1 promotes the processing and secretion of the pro-inflammatory cytokines IL-1β and IL-18, and also induces a form of programmed cell death called pyroptosis (Figure 1). Ongoing work in the lab is investigating the inflammasome sensors and the importance or pyroptosis in vivo. Inflammasomes can respond to virulence traits in pathogens. We have previously shown that bacterial pathogens using type III secretion systems to intoxicate host cells are detected by the NLRC4 (previously called Ipaf) inflammasome. The host capitalizes on accidental injection of flagellin and T3SS rod proteins in order to detect these highly conserved and slowly evolving proteins (Figure 2). Thus, the errors made by pathogens permits the innate immune system to detect them. Ongoing work is designed to discover new mechanisms by which inflammasomes detect pathogens, including Salmonella (which cause Typhoid fever or diarrhea), Burkholderia (a potential biologic weapon and emerging infectious disease in southeast Asia), and Listeria (which causes serious infections in newborns and pregnant women). Caspase-1 induces pyroptosis, a form of programmed cell death that is distinct from, and conceptually opposite to, apoptosis. We presented the first evidence that pyroptosis is a critical defense mechanism in vivo during infection (Figure 3), and that pyroptotic cell death can result in complete resistance to an otherwise dangerous infection. Continuing work in the lab will identify the mechanisms by which pyroptosis occurs and investigate the role pyroptosis plays in inflammatory and infectious diseases.
Publications
Miao, E.A., J.V. Rajan, and A. Aderem, Caspase-1 induced pyroptotic cell death. Immunol Rev, 2011: p. in press (inquire for pre-publication copy). Invited review Miao, E.A. and J.V. Rajan, Salmonella and Caspase-1: a complex interplay of detection and evasion. Front. Microbio, 2011: p. in press (inquire for pre-publication copy). Invited review Warren, S.E., D.P. Mao, J.V. Rajan, E.A. Miao†, and A. Aderem†, Generation of a Listeria monocytogenes vaccine strain by overexpression of NLRC4 agonists. Eur J Immunol, 2011: p. in press. Rajan, J.V., D. Rodriguez, E.A. Miao†, and A. Aderem†, The NLRP3 inflammasome detects EMCV and VSV infection. J Virol, 2011. 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, Caspase-1-induced pyroptosis is an innate immune effector mechanism against intracellular bacteria. Nat Immunol, 2010. 11(12): p. 1136-42. *, # Miao, E.A., D.P. Mao, N. Yudkovsky, R. Bonneau, C.G. Lorang, S.E. Warren, I.A. Leaf, and A. Aderem, Innate immune detection of the type III secretion apparatus through the NLRC4 inflammasome. Proc Natl Acad Sci U S A, 2010. 107(7): p. 3076-80. Miao, E.A. and S.E. Warren, Innate immune detection of bacterial virulence factors via the NLRC4 inflammasome. J Clin Immunol, 2010. 30(4): p. 502-6. Invited review Warren, S.E., A. Armstrong, M.K. Hamilton, D.P. Mao, I.A. Leaf, E.A. Miao†, and A. Aderem†, Cutting edge: Cytosolic bacterial DNA activates the inflammasome via Aim2. J Immunol, 2010. 185(2): p. 818-21. Rajan, J.V., S.E. Warren, E.A. Miao†, and A. Aderem†, Activation of the NLRP3 inflammasome by intracellular poly I:C. FEBS Lett, 2010. 584(22): p. 4627-32. Warren, S.E., D.P. Mao, A.E. Rodriguez, E.A. Miao†, and A. Aderem†, Multiple Nod-like receptors activate caspase 1 during Listeria monocytogenes infection. J Immunol, 2008. 180(11): p. 7558-64. Miao, E.A., R.K. Ernst, M. Dors, D.P. Mao, and A. Aderem, Pseudomonas aeruginosa activates caspase 1 through Ipaf. Proc Natl Acad Sci U S A, 2008. 105(7): p. 2562-7. Miao, E.A., E. Andersen-Nissen, S.E. Warren, and A. Aderem, TLR5 and Ipaf: dual sensors of bacterial flagellin in the innate immune system. Semin Immunopathol, 2007. 29(3): p. 275-88. Invited review Miao, E.A., C.M. Alpuche-Aranda, M. Dors, A.E. Clark, M.W. Bader, S.I. Miller, and A. Aderem, Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1beta via Ipaf. Nat Immunol, 2006. 7(6): p. 569-75. *
Figure 1. Inflammasomes detect cytosolic perturbations. IL-1β and IL-18 secretion is regulated in a two step fashion. Their transcription is induced by Toll-like receptors, which detect extracellular microbe associated molecular patterns such as LPS. After transcription, pro-IL-1β and pro-IL-18 are held in reserve in the cytosol, unlike other cytokines and chemokines which are secreted after production. Inflammasomes regulate a proteolytic processing step that is required for IL-1β and IL-18 to be secreted. Inflammasomes, most of which are Nod-like receptors (NLRs) detect cytosolic perturbations. These may be microbial products that enter the cytosol (e.g. flagellin), or perturbations to normal cytosolic function caused by infection (e.g. toxins). Inflammasomes activate Caspase-1, a protease that cleaves the cytokines IL-1β and IL-18 to their mature and secreted forms, and also promotes a form of programmed cell death called pyroptosis. Adapted from Miao and Rajan, Front. Micro. 2011.
Figure 2. NLRC4 detects cytosolic flagellin and rod proteins. Type III secretion systems (T3SS) are virulence factors used by numerous Gram-negative pathogens to deliver effector molecules to the cytosol of host cells. These effectors reprogram host cell physiology to the benefit of the pathogen. While T3SS is very efficient in selecting and transporting the dedicated effector proteins, it occasionally translocates other proteins. Two proteins that are mistakenly transferred are flagellin and the rod component of the T3SS apparatus. Macrophages and dendritic cells are able to detect T3SS activity by capitalizing on these mistakes made by the apparatus, detecting flagellin and rod protein via the cytosolic sensor NLRC4. Flagellin and rod are good targets for innate immune detection because they are relatively highly conserved and slow to evolve, unlike the effector proteins, which are variable between pathogens. Salmonella species express the SPI1 T3SS in the gut that is detected by NLRC4, but have evolved to evade this detection during the systemic phase of infection, when they replicate within macrophages. Salmonella express a different T3SS apparatus, SPI2, with a rod component that is not detected by NLRC4, and they repress flagellin expression. EC eukaryotic cytosol, PM plasma membrane, EX extracellular space, OM bacterial outer membrane, IM bacterial inner membrane, BC bacterial cytosol. Adapted from Miao and Rajan, Front Micro 2011.
Figure 3. Pyroptosis is a potent innate immune effector mechanism in vivo. Caspase-1 activation triggers pyroptotic cell death in macrophages and dendritic cells. Like apoptosis and unlike necrosis/oncosis, pyroptosis is programmed, meaning that it requires the activation of specific caspases. Like necrosis/oncosis and unlike apoptosis, pyroptosis is lytic. Intracellular pathogens that replicate within macrophages, such as S. typhimurium, must effectively evade pyroptosis in order to stay within an infected cell. Otherwise, detection by the inflammasome activates Caspase-1 and triggers pyroptosis, which releases the pathogen to the extracellular space. Once in the extracellular environment, the pathogen is exposed to additional clearance mechanisms, including phagocytosis and killing by neutrophils. Adapted from Miao et al., Nat Immunol 2010. |
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