Mary C. Dinauer, M.D., Ph.D.

Professor
Pediatrics
Hematology/Oncology
Pathology and Immunology

Immunology Program
Molecular Microbiology and Microbial Pathogenesis Program
Molecular Cell Biology Program

  • 314-286-0542

  • 314-286-2893

  • 8208

  • MPRB 4106

  • mdinauer@wustl.edu

  • immunodeficiency, inflammation, ROS, macrophage, molecular medicine, neutrophil, Aspergillus, fungus, autoimmunity, immunology

  • Role of leukocyte NADPH oxidase in innate immunity, inflammation, and autoimmunity

Research Abstract:

Dr. Dinauer studies the superoxide-generating leukocyte NADPH oxidase. Inactivating mutations in this enzyme result in chronic granulomatous disease (CGD), a primary immunodeficiency associated with recurrent bacterial and fungal infections as well as a variety of chronic inflammatory disorders, including inflammatory bowel disease and discoid lupus. These symptoms reflect the dual importance of the NADPH oxidase both for microbial killing and for negatively regulating cellular processes that limit inflammation by redox mechanisms. Moreover, hypomorphic NADPH oxidase gene variants are now linked to inflammatory bowel disease and autoimmunity.

Research interests are focused on the role of leukocyte oxidant production in the response to microbial pathogens, sterile inflammation, and predisposition to autoimmunity.
Experimental approaches involve a combination of molecular and cell biology assays on human and mouse cells and use of mouse models, including recently developed mice lacking the NADPH oxidase in specific blood cell lineages. Current areas of study are a) host response to Aspergillus fumigatus, an opportunistic pathogen that is a major pathogen in CGD, likely reflecting both impaired fungicidal activity and excessive inflammation b) NADPH oxidase regulation of sterile inflammation and removal of apoptotic cells and c) synergy of NADPH oxidase deficiency with other lupus pre-disposing genes.

Selected Publications:

Bagaitkar J*, Huang J*, Zeng MY*, Pech NK, Monlish DA, Perez-Zapata LJ, Miralda I, Schuettpelz LG, and Dinauer MC *Equal contributions. NADPH oxidase activation regulates apoptotic neutrophil clearance by murine macrophages. Blood. 2018 May 24;131(21)2367-2378. PMID: 29618478. PMCID: PMC5969376.

Bagaitkar J, Barbu EA, Perez-Zapata LJ, Austin A, Huang G, Pallat S, Dinauer MC. PI(3)P-p40phox binding regulates NADPH oxidase activation in mouse macrophages and magnitude of inflammatory responses in vivo. J Leukoc Biol. 2017 Feb;101(2):449-457. PMID: 27543673

Jacob CO, Yu N, Yoo DG, Perez-Zapata LJ, Barbu EA, Kaplan MJ, Purmalek M, Pingel JT, Idol RA, Dinauer MC. Haploinsufficiency of NADPH oxidase subunit NCF2 is sufficient to accelerate full-blown lupus in NZM.2328 mice. Arthritis Rheumatol. 2017 Aug;69(8):1647-1660. PMID:28471497.

Bagaitkar J, Pech NK, Ivanov S, Austin A, Zeng MY, Pallat S, Huang G, Randolph GJ, Dinauer MC. NADPH oxidase controls neutrophilic response to sterile inflammation in mice by regulating IL-1α/G-CSF axis. Blood. 2015 Dec 17;126(25):2724-33. PMID: 26443623. PMCID: PMC4683333

Zeng MY, Pham D, Bagaitkar J, Liu J, Otero K, Shan M, Wynn TA, Brombacher F, Brutkiewicz RR, Kaplan MH, Dinauer MC. An efferocytosis-induced, IL-4-dependent macrophage-iNKT cell circuit suppresses sterile inflammation and is defective in murine CGD. Blood. 2013 Feb 20. PMID: 23426944; PMCID: PMC3637016.

Casbon AJ, Long ME, Dunn KW, Allen LA, Dinauer MC. Effects of IFN-γ on intracellular trafficking and activity of macrophage NADPH oxidase flavocytochrome b558. J Leukoc Biol. 2012 Oct;92(4):869-82. PMID: 22822009; PMCID: PMC3441311.

Jacob CO, Eisenstein M, Dinauer MC, Ming W, Liu Q, John S, Quismorio FP Jr, Reiff A, Myones BL, Kaufman KM, McCurdy D, Harley JB, Silverman E, Kimberly RP, Vyse TJ, Gaffney PM, Moser KL, Klein-Gitelman M, Wagner-Weiner L, Langefeld CD, Armstrong DL, Zidovetzki R. Lupus-associated causal mutation in neutrophil cytosolic factor 2 (NCF2) brings unique insights to the structure and function of NADPH oxidase.Proc Natl Acad Sci U S A. 2012 Jan 10;109(2):E59-67.PMCID: PMC3258621.

Bustamante J, Arias AA, Vogt G, Picard C, Galicia LB, Prando C, Grant AV, Marchal CC, Hubeau M, Chapgier A, de Beaucoudrey L, Puel A, Feinberg J, Valinetz E, Jannire L, Besse C, Boland A, Brisseau JM, Blanche S, Lortholary O, Fieschi C, Emile JF, Boisson-Dupuis S, Al-Muhsen S, Woda B, Newburger PE, Condino-Neto A, Dinauer MC, Abel L, Casanova JL. Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease. Nat Immunol. 2011 Mar;12(3):213-21.PMCID: PMC3097900.

Li XJ, Marchal CC, Stull ND, Stahelin RV, Dinauer MC. p47phox Phox homology domain regulates plasma membrane but not phagosome neutrophil NADPH oxidase activation. J Biol Chem. 2010 Nov 5;285(45):35169-79. PMCID: PMC2966130.


Matute JD*, Arias AA*, Wright NA, Wrobel I, Waterhouse CC, Li XJ, Marchal CC, Stull ND, Lewis DB, Steele M, Kellner JD, Yu W, Meroueh SO, Nauseef WM, Dinauer MC. A new genetic subgroup of chronic granulomatous disease with autosomal recessive mutations in p40phox and selective defects in neutrophil NADPH oxidase activity. Blood 114 2009 (15):3009-3015. PMCID: PMC2759653.*(equal contributions)

Casbon AJ, Allen LA, Dunn KW, Dinauer MC. Macrophage NADPH oxidase flavocytochrome b localizes to the plasma membrane and Rab11-positive recycling endosomes. J Immunol 2009 182:2325-39. PMCID: PMC2666390.

Last Updated: 8/9/2018 10:10:42 AM

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