Molecular Signaling Section
Established in 1997
David H. McDermott, M.D.
Associate Research Physician
Contact: For contact information, search the NIH Enterprise Directory.
Provides direct clinical care to patients at NIH Clinical Center
Major Areas of Research
- Immunodeficiency / Neutropenia
- Immunogenetics of the Chemokine System
- Infectious Disease Susceptibility
- WHIMS (Warts, Hypogammaglobulinemia, Infections, and Myelokathexis Syndrome)
- G6PC3 deficiency
- SASH3 deficiency
Program Description
The focus of our program is currently on the identification, diagnosis, and treatment of various primary immunodeficiencies especially as related to the chemotactic cytokine (chemokine) system which directs the migration, adhesion, activation, and function of leukocytes. We focus on WHIMS (Warts, Hypogammaglobulinemia, Infections, and Myelokathexis Syndrome) which is due to autosomal dominant gain-of-function mutations in the CXCL12 chemokine receptor and HIV coreceptor known as CXCR4. We are repurposing a small molecule CXCR4 antagonist to treat this disorder and working on gene therapy to cure the disease as we have found that hematopoietic stem cells that lack one copy of CXCR4 have a selective bone marrow engraftment advantage. We are also working on a metabolic cause of severe congenital neutropenia and neutrophil dysfunction known as G6PC3 deficiency and attempting to repurpose empagliflozin to reduce the impact of a toxic metabolite of a dietary sugar that accumulates in leukocytes in this autosomal recessive immunodeficiency. Finally, in collaboration with Gigi Notarangelo’s group in NIAID, we recently discovered a novel immunodeficiency syndrome known as SASH3 immunodeficiency and are working on understanding the mechanism of the susceptibility to infectious diseases and autoimmunity that results from this X-linked recessive disorder.
Biography
Education
M.D., 1992, University of Virginia
B.A., 1987, University of Virginia
Dr. McDermott obtained a B.A. degree from the University of Virginia in 1987 and an M.D. from the University of Virginia in 1992. He trained in internal medicine at the University of Virginia Health Science Center from 1992 to 1995 and in infectious diseases at NIAID from 1995 to 1998 and is board certified in both. He began his medical research career as a Howard Hughes Medical Institute Research Scholar in the Bacterial Diseases Section of the NIAID Laboratory of Clinical Investigation in 1989 and returned to the NIH in 1995 as a clinical associate and continued as a research fellow. He became an assistant research physician in 2005 and was promoted to associate research physician in 2019. He has received 3 NIAID Merit Awards and 2 Bench-to-Bedside Awards for his research which has resulted in more than 75 publications with over 5000 citations.
Clinical Studies
A Phase 1 Study of Empagliflozin as a Treatment for Severe Congenital Neutropenia due to G6PC3 Deficiency: NCT05078879 Keywords: G6PC3
NIH Protocol #000236-I
A Phase III, Double-blind, Randomized, Crossover Study of Plerixafor Versus G-CSF in the Treatment of Patients with WHIM Syndrome: NCT02231879
Keywords: WHIM or WHIM syndrome
NIAID Protocol #14-I-0185
A Phase I Study of Mozobil in the Treatment of Patients with WHIMS: NCT00967785
Keywords: WHIM or WHIMS
NIAID Protocol #09-I-0200
Screening and Baseline Assessment of Patients with Abnormalities of Immune Function: NCT00128973
Keywords: immunodeficiency screening
NIAID Protocol #05-I-0213
Establishing Fibroblast-derived Cell Lines from Skin Biopsies of Patients with Immunodeficiency or Immunodysregulation Disorders: NCT00895271
Keywords:fibroblast biopsy
NIAID Protocol #09-I-0133
Selected Publications
Delmonte OM, Bergerson JRE, Kawai T, Kuehn HS, McDermott DH, Cortese I, Zimmermann MT, Dobbs AK, Bosticardo M, Fink D, Majumdar S, Palterer B, Pala F, Dsouza NR, Pouzolles M, Taylor N, Calvo KR, Daley SR, Velez D, Agharahimi A, Myint-Hpu K, Dropulic LK, Lyons JJ, Holland SM, Freeman AF, Ghosh R, Similuk MB, Niemela JE, Stoddard J, Kuhns DB, Urrutia R, Rosenzweig SD, Walkiewicz MA, Murphy PM, Notarangelo LD. SASH3 variants cause a novel form of X-linked combined immunodeficiency with immune dysregulation. Blood. 2021 Sep 23;138(12):1019-1033.
Gao JL, Owusu-Ansah A, Paun A, Beacht K, Yim E, Siwicki M, Yang A, Liu Q, McDermott DH, Murphy PM. Low-level Cxcr4-haploinsufficient HSC engraftment is sufficient to correct leukopenia in WHIM syndrome mice. JCI Insight. 2019 Dec 19;4(24):e132140.
McDermott DH, Pastrana DV, Calvo KR, Pittaluga S, Velez D, Cho E, Liu Q, Trout HH 3rd, Neves JF, Gardner PJ, Bianchi DA, Blair EA, Landon EM, Silva SL, Buck CB, Murphy PM. Plerixafor for the Treatment of WHIM Syndrome. N Engl J Med. 2019 Jan 10;380(2):163-170.
McDermott DH, Gao JL, Liu Q, Siwicki M, Martens C, Jacobs P, Velez D, Yim E, Bryke CR, Hsu N, Dai Z, Marquesen MM, Stregevsky E, Kwatemaa N, Theobald N, Long Priel DA, Pittaluga S, Raffeld MA, Calvo KR, Maric I, Desmond R, Holmes KL, Kuhns DB, Balabanian K, Bachelerie F, Porcella SF, Malech HL, Murphy PM. Chromothriptic cure of WHIM syndrome. Cell. 2015 Feb 12;160(4):686-699.
McDermott DH, De Ravin SS, Jun HS, Liu Q, Priel DA, Noel P, Takemoto CM, Ojode T, Paul SM, Dunsmore KP, Hilligoss D, Marquesen M, Ulrick J, Kuhns DB, Chou JY, Malech HL, Murphy PM. Severe congenital neutropenia resulting from G6PC3 deficiency with increased neutrophil CXCR4 expression and myelokathexis. Blood. 2010 Oct 14;116(15):2793-802.
McDermott DH, Zimmerman PA, Guignard F, Kleeberger CA, Leitman SF, Murphy PM. CCR5 promoter polymorphism and HIV-1 disease progression. Multicenter AIDS Cohort Study (MACS). Lancet. 1998 Sep 12;352(9131):866-70.