As a NIAID clinician, my main focus has been on the diagnosis, evaluation and management of individuals with defined and undefined primary immunodeficiencies (PIDs) with a particular focus on those with hyper IgE syndromes. STAT3 mutated Hyper IgE syndrome (STAT3 DN; Job’s syndrome) is associated with eczematous dermatitis, recurrent boils, recurrent sinopulmonary infections, and multiple connective tissues, skeletal and vascular abnormalities. This is a rare primary immune deficiency, and our center allows us to study the largest cohort in the US, and likely in the world. We currently follow more than 100 individuals with STAT3 DN and provide clinical care to many when well and during acute illnesses. Through laboratory collaborations over the years, we have sought to understand STAT3’s role on human immunity, airway infection susceptibility and wound and vascular remodeling. Although our understanding of the pathogenesis of STAT3 has increased in recent years, there are still many unresolved questions regarding the pathogenesis of the varied features and the optimal therapies, including the role of hematopoietic stem cell transplantation and gene editing.
Natural History, Management, and Genetics of the Hyperimmunoglobulin E Recurrent Infection Syndrome (HIES) NCT00006150
Detection and Characterization of Infections and Infection Susceptibility NCT00404560
Study of Mycobacterial Infections NCT00018044
Detection and Characterization of Host Defense Defects NCT00001355
Desai JV, Urban A, Swaim DZ, Colton B, Kibathi LW, Ferrè EMN, Stratton P, Merideth MA, Hunsberger S, Matkovits T, Mannino R, Holland SM, Tramont E, Lionakis MS, Freeman AF. Efficacy of Cochleated Amphotericin B in Mouse and Human Mucocutaneous Candidiasis. Antimicrob Agents Chemother. 2022 Jul 19;66(7):e0030822.
Delmonte OM, Bergerson JRE, Burbelo PD, Durkee-Shock JR, Dobbs K, Bosticardo M, Keller MD, McDermott DH, Rao VK, Dimitrova D, Quiros-Roldan E, Imberti L, Ferrè EMN, Schmitt M, Lafeer C, Pfister J, Shaw D, Draper D, Truong M, Ulrick J, DiMaggio T, Urban A, Holland SM, Lionakis MS, Cohen JI, Ricotta EE, Notarangelo LD, Freeman AF. Antibody responses to the SARS-CoV-2 vaccine in individuals with various inborn errors of immunity. J Allergy Clin Immunol. 2021 Nov;148(5):1192-1197.
Parisi X, Bergerson J, Urban A, Darnell D, Stratton P, Freeman AF. Obstetric and Gynecological Care in Patients with STAT3-Deficient Hyper IgE Syndrome. J Clin Immunol. 2020 Oct;40(7):1048-1050.
Freeman AF, Milner JD. The Child with Elevated IgE and Infection Susceptibility. Curr Allergy Asthma Rep. 2020 Aug 24;20(11):65.
Dmitrieva NI, Walts AD, Nguyen DP, Grubb A, Zhang X, Wang X, Ping X, Jin H, Yu Z, Yu ZX, Yang D, Schwartzbeck R, Dalgard CL, Kozel BA, Levin MD, Knutsen RH, Liu D, Milner JD, López DB, O'Connell MP, Lee CR, Myles IA, Hsu AP, Freeman AF, Holland SM, Chen G, Boehm M. Impaired angiogenesis and extracellular matrix metabolism in autosomal-dominant hyper-IgE syndrome. J Clin Invest. 2020 Aug 3;130(8):4167-4181.
Olbrich P, Freeman AF. STAT1 and STAT3 mutations: important lessons for clinical immunologists. Expert Rev Clin Immunol. 2018 Dec;14(12):1029-1041.
Hyper IgE Syndromes
Diagnosis and Treatment of Inborn errors of immunity
Susceptibility to Mycobacteria
Howard E. Boudreau, Ph.D.
We are currently investigating the role of mutant p53-induced NOX4 on the cancer cell secretome, and the effects NOX4-derived reactive oxygen species have on the inflammatory tumor microenvironment.
Ma WF, Boudreau HE, Leto TL. Pan-Cancer Analysis Shows TP53 Mutations Modulate the Association of NOX4 with Genetic Programs of Cancer Progression and Clinical Outcome. Antioxidants (Basel). 2021 Feb 4;10(2):235.
Boudreau HE, Leto TL. Model Systems to Investigate NOX-Dependent Cell Migration and Invasiveness. Methods Mol Biol. 2019;1982:473-485.
Sugamata R, Donko A, Murakami Y, Boudreau HE, Qi CF, Kwon J, Leto TL. Duox1 Regulates Primary B Cell Function under the Influence of IL-4 through BCR-Mediated Generation of Hydrogen Peroxide. J Immunol. 2019 Jan 15;202(2):428-440.
Boudreau HE, Ma WF, Korzeniowska A, Park JJ, Bhagwat MA, Leto TL. Histone modifications affect differential regulation of TGFβ- induced NADPH oxidase 4 (NOX4) by wild-type and mutant p53. Oncotarget. 2017 Jul 4;8(27):44379-44397.
Boudreau HE, Casterline BW, Burke DJ, Leto TL. Wild-type and mutant p53 differentially regulate NADPH oxidase 4 in TGF-β-mediated migration of human lung and breast epithelial cells. Br J Cancer. 2014 May 13;110(10):2569-82.
- NADPH oxidase (NOX) enzyme function
- Inflammation
- Wound healing
- Cancer metastasis
Suk See De Ravin, M.D., Ph.D.
Dr. De Ravin’s primary goal is to develop novel gene therapy and cell therapy approaches for treatment of Inborn Errors of Immunity (IEI) /Primary Immunodeficiency Diseases (PID). Advances in genomic diagnosis and immune-phenotype characterization within National Institutes of Allergy and Infectious Diseases identifies many individuals who will benefit from gene and cell therapy. Current gene therapy for IEI (e.g., X-linked SCID, Chronic Granulomatous Disease (CGD) using lentivectors) has provided clinical benefit to multiple patients. However, the risk semi-random vector insertion causing insertional oncogenesis and the lack of physiological gene expression from inserted exogenous transgenes leave room for improvement. To address these concerns, Dr. De Ravin is working on targeted approaches to insert therapeutic genes in hematopoietic stem and progenitor cells for future gene therapy. Programmable CRISPR-Cas9 nuclease systems can deliver corrective genes or repair mutations efficiently. However, this approach carries risks of genotoxicity although there are mitigating agents. Base editing that side-steps risks associated with double strand DNA breaks and the dependence on homology-directed repair is another promising approach for gene therapy for the near future. For patients with infections difficult to control with current antimicrobials, mRNA transfection of autologous primary cells such as granulocytes provide hopes for a transient therapeutic approach. A better understanding of the immune-phenotype allows rational designs for short-term disease control and ultimately long-term treatment of disease with ideal gene therapy approach.
NADPH Oxidase Correction in mRNA-transfected Granulocyte-enriched Cells in Chronic Granulomatous Disease (CGD): NCT05189925
Recruitment and Apheresis Collection of Peripheral Blood Hematopoietic Stem Cells, Mononuclear Cells and Granulocytes: NCT00001405
Lentiviral Gene Transfer for Treatment of Children Older Than Two Years of Age With X-Linked Severe Combined Immunodeficiency (XSCID): NCT01306019
Screening and Baseline Assessment of Patients with Abnormalities of Immune Function
A Phase 1 Study to Evaluate the Safety and Tolerability of Tandemly-purified Allogeneic CD34+CD90+ HSC Administered Following Conditioning with JAS 191 to Achieve Engraftment and Immune Reconstitution in Patients with SCID
Brault J, Liu T, Bello E, Liu S, Sweeney CL, Meis RJ, Koontz S, Corsino C, Choi U, Vayssiere G, Bosticardo M, Dowdell K, Lazzarotto CR, Clark AB, Notarangelo LD, Ravell JC, Lenardo MJ, Kleinstiver BP, Tsai SQ, Wu X, Dahl GA, Malech HL, De Ravin SS. CRISPR-targeted MAGT1 insertion restores XMEN patient hematopoietic stem cells and lymphocytes. Blood. 2021 Dec 30;138(26):2768-2780.
De Ravin SS, Brault J, Meis RJ, Liu S, Li L, Pavel-Dinu M, Lazzarotto CR, Liu T, Koontz SM, Choi U, Sweeney CL, Theobald N, Lee G, Clark AB, Burkett SS, Kleinstiver BP, Porteus MH, Tsai S, Kuhns DB, Dahl GA, Headey S, Wu X, Malech HL. Enhanced homology-directed repair for highly efficient gene editing in hematopoietic stem/progenitor cells. Blood. 2021 May 13;137(19):2598-2608.
Brault J, Meis RJ, Li L, Bello E, Liu T, Sweeney CL, Koontz SM, Dowdell K, Theobald N, Lee J, Allen C, Clark AB, Ravell JC, Lenardo MJ, Dahl GA, Malech HL, De Ravin SS. MAGT1 messenger RNA-corrected autologous T and natural killer cells for potential cell therapy in X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection and neoplasia disease. Cytotherapy. 2021 Mar;23(3):203-210.
De Ravin SS, Brault J, Meis RJ, Li L, Theobald N, Bonifacino AC, Lei H, Liu TQ, Koontz S, Corsino C, Zarakas MA, Desai JV, Clark AB, Choi U, Metzger ME, West K, Highfill SL, Kang E, Kuhns DB, Lionakis MS, Stroncek DF, Dunbar CE, Tisdale JF, Donahue RE, Dahl GA, Malech HL. NADPH oxidase correction by mRNA transfection of apheresis granulocytes in chronic granulomatous disease. Blood Adv. 2020 Dec 8;4(23):5976-5987.
De Ravin SS, Wu X, Moir S, Anaya-O'Brien S, Kwatemaa N, Littel P, Theobald N, Choi U, Su L, Marquesen M, Hilligoss D, Lee J, Buckner CM, Zarember KA, O'Connor G, McVicar D, Kuhns D, Throm RE, Zhou S, Notarangelo LD, Hanson IC, Cowan MJ, Kang E, Hadigan C, Meagher M, Gray JT, Sorrentino BP, Malech HL, Kardava L. Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency. Sci Transl Med. 2016 Apr 20;8(335):335ra57.
De Ravin SS, Reik A, Liu PQ, Li L, Wu X, Su L, Raley C, Theobald N, Choi U, Song AH, Chan A, Pearl JR, Paschon DE, Lee J, Newcombe H, Koontz S, Sweeney C, Shivak DA, Zarember KA, Peshwa MV, Gregory PD, Urnov FD, Malech HL. Targeted gene addition in human CD34(+) hematopoietic cells for correction of X-linked chronic granulomatous disease. Nat Biotechnol. 2016 Apr;34(4):424-9.
- Gene therapy
- Inborn Errors of Immunity/Primary Immunodeficiency Diseases; Chronic Granulomatous Disease, X-linked Severe Combined Immunodeficiency, XMEN, WHIM, XLA, STAT3, STAT1, CTLA4.
Farinaz Safavi, M.D., Ph.D.
Inborn Errors of Immunity (IEIs) are genetic disorders of the immune system with clinical manifestations of infection and autoinflammatory syndrome. Neurological disorders are one of the common causes of irreversible morbidity and mortality in patients with IEIs. Neuroinflammatory, neuroinfectious and neurodegenerative diseases have been reported extensively in this patient population but the role of immune related gene defects on development, function and immunoregulation of nervous system is still unknown.
The NeuroImmunopathogenesis Unit performs an integrated bench to bedside research to better understand the role of immunodeficiencies in nervous system. Taking a comprehensive approach to evaluate profile and function of immune cells in both blood and cerebrospinal fluid, the most adjacent cells to nervous system, provides valuable understanding about dynamic of immune cells and responses in CNS immune-compartment paving the path to find more targeted therapeutics. By using induced pluripotent stem cell technology, the unit also investigates the role of immune related gene defects in development and function of human neurons and glia to find underlying cellular and molecular pathways in immunodeficient patients with neurological disorders.
Furthermore, rare neuroinfectious, neuroinflammatory and neurodegenerative diseases with atypical clinical features can be a manifestation of immune related gene defects. Our holistic clinical and basic immunology, neuroscience and genetic approach facilitates to better understand the underlying mechanisms of these presentations to clarify diagnosis and treatments of this patients’ complex and often refractory to treatment neurological diseases.
Lee MH, Perl DP, Steiner J, Pasternack N, Li W, Maric D, Safavi F, Horkayne-Szakaly I, Jones R, Stram MN, Moncur JT, Hefti M, Folkerth RD, Nath A. Neurovascular injury with complement activation and inflammation in COVID-19. Brain. 2022 Jul 5:awac151.
Safavi F, Thome R, Li Z, Wang L, Rasouli J, Ciric B, Zhang GX, Rostami A. A serine protease inhibitor induces type 1 regulatory T cells through IFN-γ/STAT1 signaling. Cell Mol Immunol. 2020 Sep;17(9):1004-1006.
Safavi F, Nath A. Silencing of immune activation with methotrexate in patients with COVID-19. J Neurol Sci. 2020 Aug 15;415:116942.
Safavi F, Thome R, Li Z, Zhang GX, Rostami A. Dimethyl fumarate suppresses granulocyte macrophage colony-stimulating factor-producing Th1 cells in CNS neuroinflammation. Neurol Neuroimmunol Neuroinflamm. 2020 May 5;7(4):e729.
Rasouli J, Ciric B, Imitola J, Gonnella P, Hwang D, Mahajan K, Mari ER, Safavi F, Leist TP, Zhang GX, Rostami A. Expression of GM-CSF in T Cells Is Increased in Multiple Sclerosis and Suppressed by IFN-β Therapy. J Immunol. 2015 Jun 1;194(11):5085-93.
El-Behi M, Ciric B, Dai H, Yan Y, Cullimore M, Safavi F, Zhang GX, Dittel BN, Rostami A. The encephalitogenicity of T(H)17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM-CSF. Nat Immunol. 2011 Jun;12(6):568-75.
- Neurological manifestations of primary and acquired immunodeficiency
- Role of immune related gene defects in neurons and glial cell function
- The effect of host immune defects on CNS immune-compartment
- Investigate the role of Inborn Errors of Immunity (IEIs) in patients with atypical neuroinflammatory, neuroinfectious and neurodegenerative diseases
Christa S. Zerbe, M.D., M.S.
As a Senior Clinician, Dr. Zerbe focuses on the clinical care of patients with CGD and acquired anti-cytokine antibody syndromes. Her research includes studies in patients with anti-cytokine antibodies both nationally and internationally in Thailand continuing the research and treatment of patients who suffer from these syndromes in order to further our understanding of non-HIV acquired immunodeficiency. Additionally, Dr. Zerbe oversees the care and research regarding patients with and affected carriers of the gene resulting in Chronic Granulomatous Disease. Her collaboration with the NIDDK and with outside collaborators resulted in a UO1 grant as well as several protocols looking at therapies aimed at the inflammatory complications in this disease.
Mycobacterial and Opportunistic Infections in HIV-Negative Thai and Taiwanese Patients Associated With Autoantibodies to Interferon-gamma NCT00814827
Elemental Diet for Treatment of Inflammatory Bowel Disease in Patients With Chronic Granulomatous Disease NCT03983837
Safety and Efficacy of Tofacitinib for Chronic Granulomatous Disease With Inflammatory Complications NCT05104723
Microbial, Immune, and Metabolic Perturbations by Antibiotics (MIME Study) NCT02707042
Falcone EL, Han Y, Kreuzburg S, Heller T, Church JA, Grou C, Calderon V, Subramanian P, Deming C, Conlan S, Segre JA, Holland SM, Zerbe CS. Exclusive enteral nutrition induced sustained changes in the microbiota and improved inflammatory bowel disease in a pediatric patient with chronic granulomatous disease. J Allergy Clin Immunol Pract. 2021 Feb;9(2):1011-1014.e2.
Bhattacharya S, Marciano BE, Malech HL, Quezado M, Holland SM, De Ravin SS, Zerbe CS, Heller T. Safety and Efficacy of Ustekinumab in the Inflammatory Bowel Disease of Chronic Granulomatous Disease. Clin Gastroenterol Hepatol. 2022 Feb;20(2):461-464.e2.
Marciano BE*, Zerbe CS*, Falcone EL, Ding L, DeRavin SS, Daub J, Kreuzburg S, Yockey L, Hunsberger S, Foruraghi L, Barnhart LA, Matharu K, Anderson V, Darnell DN, Frein C, Fink DL, Lau KP, Long Priel DA, Gallin JI, Malech HL, Uzel G, Freeman AF, Kuhns DB, Rosenzweig SD, HollandSM. X-linked carriers of chronic granulomatous disease: Illness, lyonization, and stability. J Allergy Clin Immunol. 2018 Jan;141(1):365-371
Rocco JM, Rosen LB, Hong GH, Treat J, Kreuzburg S, Holland SM, Zerbe CS. Bortezomib treatment for refractory nontuberculous mycobacterial infection in the setting of interferon gamma autoantibodies. J Transl Autoimmun. 2021 May 4;4:100102.
Hong GH, Ortega-Villa AM, Hunsberger S, Chetchotisakd P, Anunnatsiri S, Mootsikapun P, Rosen LB, Zerbe CS, Holland SM. Natural History and Evolution of Anti-Interferon-γ Autoantibody-Associated Immunodeficiency Syndrome in Thailand and the US. Clin Infect Dis. 2019 Aug 20.
Moutsopoulos NM, Zerbe CS, Wild T, Dutzan N, Brenchley L, DiPasquale G, Uzel G, Axelrod KC, Lisco A, Notarangelo LD, Hajishengallis G, Notarangelo LD, Holland SM.,Interleukin-12 and Interleukin-23 Blockade in Leukocyte Adhesion Deficiency Type 1 N Engl J Med. 2017 Mar 23;376(12):1141-1146.
- Chronic Granulomatous Disease and the Inflammatory and Infectious complications
- Carriers of X-linked CGD
- Anti-Cytokine Autoantibody Diseases
- Disseminated Non-Tuberculosis Mycobacterial Infections
Veronique Nussenblatt, M.D, Sc.M., M.H.S
Major Areas of Research
- COVID-19
Biography
Dr. Nussenblatt received her M.D. from the University of Maryland School of Medicine and completed her internal medicine residency and infectious disease fellowship at the Johns Hopkins University School of Medicine. After completing her training, she joined the Infectious Disease faculty at The Johns Hopkins School of Medicine until she moved to Belgium where she spent two years providing clinical and scientific expertise for the development and implementation of clinical studies within two European clinical trial networks.
Program Description
Dr. Nussenblatt specialized in general infectious diseases as well as managing infections in immunocompromised hosts. She provides diagnostic and therapeutic expertise for the management of infections in patients enrolled in clinical protocols at the NIH. She has a particular interest in COVID-19 in immunocompromised patients. Dr. Nussenblatt provides clinical supervision and training of infectious disease fellows and of residents and medical students rotating on the Infectious Disease Consult Service at the NIH.
Selected Publications
- Suh GA, Lodise TP, Tamma PD, Knisely JM, Alexander J, Aslam S, Barton KD, Bizzell E, Totten KMC, Campbell JL, Chan BK, Cunningham SA, Goodman KE, Greenwood-Quaintance KE, Harris AD, Hesse S, Maresso A, Nussenblatt V, Pride D, Rybak MJ, Sund Z, van Duin D, Van Tyne D, Patel R; Antibacterial Resistance Leadership Group. Considerations for the Use of Phage Therapy in Clinical Practice. Antimicrob Agents Chemother. 2022 Mar 15;66(3):e0207121.
- Nussenblatt V, Roder AE, Das S, de Wit E, Youn JH, Banakis S, Mushegian A, Mederos C, Wang W, Chung M, Pérez-Pérez L, Palmore T, Brudno JN, Kochenderfer JN, Ghedin E. Year-long COVID-19 infection reveals within-host evolution of SARS-CoV-2 in a patient with B cell depletion. medRxiv [Preprint]. 2021 Oct 5:2021.10.02.21264267.
- Melendez-Munoz R, Marchalik R, Jerussi T, Dimitrova D, Nussenblatt V, Beri A, Rai K, Wilder JS, Barrett AJ, Battiwalla M, Childs RW, Fitzhugh CD, Fowler DH, Fry TJ, Gress RE, Hsieh MM, Ito S, Kang EM, Pavletic SZ, Shah NN, Tisdale JF, Gea-Banacloche J, Kanakry CG, Kanakry JA. Cytomegalovirus Infection Incidence and Risk Factors Across Diverse Hematopoietic Cell Transplantation Platforms Using a Standardized Monitoring and Treatment Approach: A Comprehensive Evaluation from a Single Institution. Biol Blood Marrow Transplant. 2019 Mar;25(3):577-586.
- Sigfrid L, Reusken C, Eckerle I, Nussenblatt V, Lipworth S, Messina J, Kraemer M, Ergonul O, Papa A, Koopmans M, Horby P. Preparing clinicians for (re-)emerging arbovirus infectious diseases in Europe. Clin Microbiol Infect. 2018 Mar;24(3):229-239.
- Nussenblatt V, Avdic E, Berenholtz S, Daugherty E, Hadhazy E, Lipsett PA, Maragakis LL, Perl TM, Speck K, Swoboda SM, Ziai W, Cosgrove SE. Ventilator-associated pneumonia: overdiagnosis and treatment are common in medical and surgical intensive care units. Infect Control Hosp Epidemiol. 2014 Mar;35(3):278-84.
Training Programs
Infectious Diseases Fellowship
NIH Residency Electives Program (REP)
Dr. Nussenblatt specialized in general infectious diseases as well as managing infections in immunocompromised hosts. She provides diagnostic and therapeutic expertise for the management of infections in patients enrolled in clinical protocols at the NIH. She has a particular interest in COVID-19 in immunocompromised patients. Dr. Nussenblatt provides clinical supervision and training of infectious disease fellows and of residents and medical students rotating on the Infectious Disease Consult Service at the NIH.
Suh GA, Lodise TP, Tamma PD, Knisely JM, Alexander J, Aslam S, Barton KD, Bizzell E, Totten KMC, Campbell JL, Chan BK, Cunningham SA, Goodman KE, Greenwood-Quaintance KE, Harris AD, Hesse S, Maresso A, Nussenblatt V, Pride D, Rybak MJ, Sund Z, van Duin D, Van Tyne D, Patel R; Antibacterial Resistance Leadership Group. Considerations for the Use of Phage Therapy in Clinical Practice. Antimicrob Agents Chemother. 2022 Mar 15;66(3):e0207121.
Nussenblatt V, Roder AE, Das S, de Wit E, Youn JH, Banakis S, Mushegian A, Mederos C, Wang W, Chung M, Pérez-Pérez L, Palmore T, Brudno JN, Kochenderfer JN, Ghedin E. Year-long COVID-19 infection reveals within-host evolution of SARS-CoV-2 in a patient with B cell depletion. medRxiv [Preprint]. 2021 Oct 5:2021.10.02.21264267.
Melendez-Munoz R, Marchalik R, Jerussi T, Dimitrova D, Nussenblatt V, Beri A, Rai K, Wilder JS, Barrett AJ, Battiwalla M, Childs RW, Fitzhugh CD, Fowler DH, Fry TJ, Gress RE, Hsieh MM, Ito S, Kang EM, Pavletic SZ, Shah NN, Tisdale JF, Gea-Banacloche J, Kanakry CG, Kanakry JA. Cytomegalovirus Infection Incidence and Risk Factors Across Diverse Hematopoietic Cell Transplantation Platforms Using a Standardized Monitoring and Treatment Approach: A Comprehensive Evaluation from a Single Institution. Biol Blood Marrow Transplant. 2019 Mar;25(3):577-586.
Sigfrid L, Reusken C, Eckerle I, Nussenblatt V, Lipworth S, Messina J, Kraemer M, Ergonul O, Papa A, Koopmans M, Horby P. Preparing clinicians for (re-)emerging arbovirus infectious diseases in Europe. Clin Microbiol Infect. 2018 Mar;24(3):229-239.
Nussenblatt V, Avdic E, Berenholtz S, Daugherty E, Hadhazy E, Lipsett PA, Maragakis LL, Perl TM, Speck K, Swoboda SM, Ziai W, Cosgrove SE. Ventilator-associated pneumonia: overdiagnosis and treatment are common in medical and surgical intensive care units. Infect Control Hosp Epidemiol. 2014 Mar;35(3):278-84.
Training Programs
- Infectious Diseases Fellowship
- NIH Residency Electives Program (REP)
- Clinical Electives Program (CEP)
- COVID-19
Colin L. Sweeney, Ph.D.
Major Ares of Research
- Major areas of research: Induced pluripotent stem cells (reprogramming and differentiation), Hematopoietic stem cell biology and hematopoiesis, Genome editing of stem cells
- Disease focus: Chronic Granulomatous Disease
Biography
Colin Sweeney received baccalaureate degrees in Biology and Computer Science from the University of Minnesota – Morris in 1997 and a Ph.D. from the Microbiology, Immunology, and Molecular Pathobiology program at the University of Minnesota in 2003. He received further training as a Postdoctoral Fellow in the laboratory of Dr. Stanton Gerson at Case Western Reserve University and in the laboratory of Dr. Harry Malech at NIAID, before joining Dr. Malech’s lab as a Staff Scientist in 2016.
Program Description
Colin Sweeney provides core expertise and training to laboratories in NIAID on induced pluripotent stem cells (iPSCs), including collaborations with investigators throughout NIAID to perform iPSC reprogramming of patient samples and differentiation of iPSCs into mature cell types of interest for the modeling of disease phenotypes and immune responses, as well as performing genome editing of iPSCs and other cell types with CRISPR/Cas9 for gene knockout studies, gene repair, or targeted transgene insertion. He has developed efficient iPSC reprogramming protocols using small volumes of patient blood samples or cryopreserved mononuclear cells as well as developing and utilizing iPSC differentiation protocols for production of specific cell lineages, including fibroblasts, neural stem cells, neurons, astrocytes, hematopoietic stem/progenitor cells, monocytes/macrophages, dendritic cells, and microglia. In his research as a member of the Malech lab in the Genetic Immunotherapy Section, he has utilized patient-derived iPSCs for preclinical modeling of gene therapy strategies for treatment of Chronic Granulomatous Disease (CGD), including testing of therapeutic gene vector designs and identifying critical regulatory elements within the CYBB gene that are necessary to achieve normal physiological levels of expression after gene editing for treatment of X-linked CGD, and subsequently confirmed these findings in X-linked CGD patient hematopoietic stem cells as a relevant target cell type for clinical gene therapy. In follow-up assessments of clinical trial patients receiving lentiviral vector-based gene therapy for treatment of X-linked severe combined immunodeficiency, he has utilized iPSCs derived from post-treatment patient hematopoietic stem cells to study the effects of cryptic transcript splicing from the therapeutic lentiviral vector on aberrant clonal hematopoietic outgrowth after hematopoietic stem cell transplant, to develop vector safety modifications that eliminate cryptic splice sites.
Selected Publications
De Ravin SS, Liu S, Sweeney C, Brault J, Whiting-Theobald N, Ma M, Liu T, Choi U, Lee J, Anaya-O'Brien S, Quackenbush P, Estwick T, Karra A, Docking E, Kwatemaa N, Guo S, Su L, Sun D, Zhou S, Puck J, Cowan M, Notarangelo L, Kang E, Malech H, Wu X. Lentivector cryptic splicing mediates increase in CD34+ clones expressing truncated HMGA2 in human X-linked Severe Combined Immunodeficiency. Nature Communications. In press.
Sweeney CL, Pavel-Dinu M, Choi U, Brault J, Liu T, Koontz S, Li L, Theobald N, Lee J, Bello EA, Wu X, Meis RJ, Dahl GA, Porteus MH, Malech HL, De Ravin SS. Correction of X-CGD patient HSPCs by targeted CYBB cDNA insertion using CRISPR/Cas9 with 53BP1 inhibition for enhanced homology-directed repair. Gene Ther. 2021 Jun;28(6):373-390.
Zhang ZZ, Zhang Y, He T, Sweeney CL, Baris S, Karakoc-Aydiner E, Yao Y, Ertem D, Matthews HF, Gonzaga-Jauregui C, Malech HL, Su HC, Ozen A, Smith KGC, Lenardo MJ. Homozygous IL37 mutation associated with infantile inflammatory bowel disease. Proc Natl Acad Sci U S A. 2021 Mar 9;118(10):e2009217118.
Sweeney CL, Merling RK, De Ravin SS, Choi U, Malech HL. Gene Editing in Chronic Granulomatous Disease. Methods Mol Biol. 2019;1982:623-665.
Sweeney CL, Zou J, Choi U, Merling RK, Liu A, Bodansky A, Burkett S, Kim JW, De Ravin SS, Malech HL. Targeted Repair of CYBB in X-CGD iPSCs Requires Retention of Intronic Sequences for Expression and Functional Correction. Mol Ther. 2017 Feb 1;25(2):321-330.
Sweeney CL, Teng R, Wang H, Merling RK, Lee J, Choi U, Koontz S, Wright DG, Malech HL. Molecular Analysis of Neutrophil Differentiation from Human Induced Pluripotent Stem Cells Delineates the Kinetics of Key Regulators of Hematopoiesis. Stem Cells. 2016 Jun;34(6):1513-26.
Visit PubMed for a complete publication listing.
Colin Sweeney provides core expertise and training to laboratories in NIAID on induced pluripotent stem cells (iPSCs), including collaborations with investigators throughout NIAID to perform iPSC reprogramming of patient samples and differentiation of iPSCs into mature cell types of interest for the modeling of disease phenotypes and immune responses, as well as performing genome editing of iPSCs and other cell types with CRISPR/Cas9 for gene knockout studies, gene repair, or targeted transgene insertion. He has developed efficient iPSC reprogramming protocols using small volumes of patient blood samples or cryopreserved mononuclear cells as well as developing and utilizing iPSC differentiation protocols for production of specific cell lineages, including fibroblasts, neural stem cells, neurons, astrocytes, hematopoietic stem/progenitor cells, monocytes/macrophages, dendritic cells, and microglia. In his research as a member of the Malech lab in the Genetic Immunotherapy Section, he has utilized patient-derived iPSCs for preclinical modeling of gene therapy strategies for treatment of Chronic Granulomatous Disease (CGD), including testing of therapeutic gene vector designs and identifying critical regulatory elements within the CYBB gene that are necessary to achieve normal physiological levels of expression after gene editing for treatment of X-linked CGD, and subsequently confirmed these findings in X-linked CGD patient hematopoietic stem cells as a relevant target cell type for clinical gene therapy. In follow-up assessments of clinical trial patients receiving lentiviral vector-based gene therapy for treatment of X-linked severe combined immunodeficiency, he has utilized iPSCs derived from post-treatment patient hematopoietic stem cells to study the effects of cryptic transcript splicing from the therapeutic lentiviral vector on aberrant clonal hematopoietic outgrowth after hematopoietic stem cell transplant, to develop vector safety modifications that eliminate cryptic splice sites.
De Ravin SS, Liu S, Sweeney C, Brault J, Whiting-Theobald N, Ma M, Liu T, Choi U, Lee J, Anaya-O'Brien S, Quackenbush P, Estwick T, Karra A, Docking E, Kwatemaa N, Guo S, Su L, Sun D, Zhou S, Puck J, Cowan M, Notarangelo L, Kang E, Malech H, Wu X. Lentivector cryptic splicing mediates increase in CD34+ clones expressing truncated HMGA2 in human X-linked Severe Combined Immunodeficiency. Nature Communications. In press.
Sweeney CL, Pavel-Dinu M, Choi U, Brault J, Liu T, Koontz S, Li L, Theobald N, Lee J, Bello EA, Wu X, Meis RJ, Dahl GA, Porteus MH, Malech HL, De Ravin SS. Correction of X-CGD patient HSPCs by targeted CYBB cDNA insertion using CRISPR/Cas9 with 53BP1 inhibition for enhanced homology-directed repair. Gene Ther. 2021 Jun;28(6):373-390.
Zhang ZZ, Zhang Y, He T, Sweeney CL, Baris S, Karakoc-Aydiner E, Yao Y, Ertem D, Matthews HF, Gonzaga-Jauregui C, Malech HL, Su HC, Ozen A, Smith KGC, Lenardo MJ. Homozygous IL37 mutation associated with infantile inflammatory bowel disease. Proc Natl Acad Sci U S A. 2021 Mar 9;118(10):e2009217118.
Sweeney CL, Merling RK, De Ravin SS, Choi U, Malech HL. Gene Editing in Chronic Granulomatous Disease. Methods Mol Biol. 2019;1982:623-665.
Sweeney CL, Zou J, Choi U, Merling RK, Liu A, Bodansky A, Burkett S, Kim JW, De Ravin SS, Malech HL. Targeted Repair of CYBB in X-CGD iPSCs Requires Retention of Intronic Sequences for Expression and Functional Correction. Mol Ther. 2017 Feb 1;25(2):321-330.
Sweeney CL, Teng R, Wang H, Merling RK, Lee J, Choi U, Koontz S, Wright DG, Malech HL. Molecular Analysis of Neutrophil Differentiation from Human Induced Pluripotent Stem Cells Delineates the Kinetics of Key Regulators of Hematopoiesis. Stem Cells. 2016 Jun;34(6):1513-26.
- Major areas of research: Induced pluripotent stem cells (reprogramming and differentiation), Hematopoietic stem cell biology and hematopoiesis, Genome editing of stem cells
- Disease focus: Chronic Granulomatous Disease
Ottavia Maria Delmonte, M.D., Ph.D.
Major Areas of Research
• T cell development
• T cell repertoire
• Inborn errors of immunity
• Severe combined immunodeficiency
• Combined immunodeficiency
• Immunedysregulation disorders
Program Description
Ottavia Delmonte, M.D., Ph.D., is a physician scientist at National Institute of Health, USA. She has been involved in translational research in primary immune deficiencies (PIDs) and disorders of immune dysregulation since joining the group of Dr. Luigi Notarangelo in 2016. She assists in the development and implementation of clinical research protocols studying immunologic diseases in children and adults with PID and she conducts laboratory research aimed to characterize novel forms of monogenic PIDs and dynamics of immune reconstitution after Hematopoietic Cell Transplantation and/or gene therapy. She is particularly interested in T cell repertoire abnormalities associated with inborn errors of immunity and treatment strategies for PIDs like gene editing and gene correction. In the past 2 years she has described a novel inherited combined immunodeficiency with immune-dysregulation due to SASH3 deficiency and studied T cell repertoire perturbation in multiple newly characterized genetic disorders of the immune system including CD28 and PD1 deficiency. During the COVID-19 pandemic her research focused on virus-host interaction in individuals with life-threatening COVID-19 and multisystem inflammatory disease of children (MIS-C) and on the characterization of immunization responses to SARS-CoV-2 vaccine in patients with PIDs.
Biography
She received her M.D., Ph.D. degree from the University of Turin, Italy. She completed a pediatric residency followed by a fellowship in Allergy and Immunology at Boston Children’s Hospital, Harvard University, USA. She speaks Italian and English.
Publications
- Sacco K, Castagnoli R, Vakkilainen S, Liu C, Delmonte OM, Oguz C, Kaplan IM, Alehashemi S, Burbelo PD, Bhuyan F, de Jesus AA, Dobbs K, Rosen LB, Cheng A, Shaw E, Vakkilainen MS, Pala F, Lack J, Zhang Y, Fink DL, Oikonomou V, Snow AL, Dalgard CL, Chen J, Sellers BA, Montealegre Sanchez GA, Barron K, Rey-Jurado E, Vial C, Poli MC, Licari A, Montagna D, Marseglia GL, Licciardi F, Ramenghi U, Discepolo V, Lo Vecchio A, Guarino A, Eisenstein EM, Imberti L, Sottini A, Biondi A, Mató S, Gerstbacher D, Truong M, Stack MA, Magliocco M, Bosticardo M, Kawai T, Danielson JJ, Hulett T, Askenazi M, Hu S; NIAID Immune Response to COVID Group; Chile MIS-C Group; Pavia Pediatric COVID-19 Group, Cohen JI, Su HC, Kuhns DB, Lionakis MS, Snyder TM, Holland SM, Goldbach-Mansky R, Tsang JS, Notarangelo LD. Immunopathological signatures in multisystem inflammatory syndrome in children and pediatric COVID-19. Nat Med. 2022 May;28(5):1050-1062.
- Delmonte OM, Castagnoli R, Yu J, Dvorak CC, Cowan MJ, Dávila Saldaña BJ, De Ravin SS, Mamcarz E, Chang CK, Daley SR, Griffith LM, Notarangelo LD, Puck JM. Poor T-cell receptor β repertoire diversity early posttransplant for severe combined immunodeficiency predicts failure of immune reconstitution. J Allergy Clin Immunol. 2022 Mar;149(3):1113-1119.
- Delmonte OM, Bergerson JRE, Burbelo PD, Durkee-Shock JR, Dobbs K, Bosticardo M, Keller MD, McDermott DH, Rao VK, Dimitrova D, Quiros-Roldan E, Imberti L, Ferrè EMN, Schmitt M, Lafeer C, Pfister J, Shaw D, Draper D, Truong M, Ulrick J, DiMaggio T, Urban A, Holland SM, Lionakis MS, Cohen JI, Ricotta EE, Notarangelo LD, Freeman AF. Antibody responses to the SARS-CoV-2 vaccine in individuals with various inborn errors of immunity. J Allergy Clin Immunol. 2021 Nov;148(5):1192-1197.
- 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.
- Béziat V, Rapaport F, Hu J, Titeux M, Bonnet des Claustres M, Bourgey M, Griffin H, Bandet É, Ma CS, Sherkat R, Rokni-Zadeh H, Louis DM, Changi-Ashtiani M, Delmonte OM, Fukushima T, Habib T, Guennoun A, Khan T, Bender N, Rahman M, About F, Yang R, Rao G, Rouzaud C, Li J, Shearer D, Balogh K, Al Ali F, Ata M, Dabiri S, Momenilandi M, Nammour J, Alyanakian MA, Leruez-Ville M, Guenat D, Materna M, Marcot L, Vladikine N, Soret C, Vahidnezhad H, Youssefian L, Saeidian AH, Uitto J, Catherinot É, Navabi SS, Zarhrate M, Woodley DT, Jeljeli M, Abraham T, Belkaya S, Lorenzo L, Rosain J, Bayat M, Lanternier F, Lortholary O, Zakavi F, Gros P, Orth G, Abel L, Prétet JL, Fraitag S, Jouanguy E, Davis MM, Tangye SG, Notarangelo LD, Marr N, Waterboer T, Langlais D, Doorbar J, Hovnanian A, Christensen N, Bossuyt X, Shahrooei M, Casanova JL. Humans with inherited T cell CD28 deficiency are susceptible to skin papillomaviruses but are otherwise healthy. Cell. 2021 Jul 8;184(14):3812-3828.e30
- Abers MS, Delmonte OM, Ricotta EE, Fintzi J, Fink DL, de Jesus AAA, Zarember KA, Alehashemi S, Oikonomou V, Desai JV, Canna SW, Shakoory B, Dobbs K, Imberti L, Sottini A, Quiros-Roldan E, Castelli F, Rossi C, Brugnoni D, Biondi A, Bettini LR, D'Angio' M, Bonfanti P, Castagnoli R, Montagna D, Licari A, Marseglia GL, Gliniewicz EF, Shaw E, Kahle DE, Rastegar AT, Stack M, Myint-Hpu K, Levinson SL, DiNubile MJ, Chertow DW, Burbelo PD, Cohen JI, Calvo KR, Tsang JS; NIAID COVID-19 Consortium, Su HC, Gallin JI, Kuhns DB, Goldbach-Mansky R, Lionakis MS, Notarangelo LD. An immune-based biomarker signature is associated with mortality in COVID-19 patients. JCI Insight. 2021 Jan 11;6(1):e144455.
Clinical Trials
- Send-In Sample Collection to Achieve Genetic and Immunologic Characterization of Primary Immunodeficiencies - NCT03610802
- Send-in sample collection for comprehensive analyses of innate and adaptive immune responses during acute COVID-19 and convalescence - NCT04582903
- Natural history, epidemiology and pathogenesis of severe HPV-related diseases (Neptune) - NCT05026138
- A Phase 1/2 Study to Evaluate the Safety, Tolerability and Efficacy, of JSP191 for Hematopoietic Cell Transplantation Conditioning to Achieve Engraftment and Immune Reconstitution in Subjects with SCID - NCT02963064
- Matched Related and Unrelated Donor Stem Cell Transplantation for Severe Combined Immune Deficiency (SCID): Busulfan-based Conditioning with h-ATG, Radiation, and Sirolimus. Associate investigator - NCT04370795
- Investigating the Mechanistic Biology of Primary Immunodeficiency Disorders - NCT03394053
- A Natural History Study of the Immune Regulation of Idiopathic Inflammatory Bowel Diseases: Crohn's Disease, Ulcerative Colitis, and Other Inflammatory Conditions of the Gut - NCT00001184
Ottavia Delmonte, M.D., Ph.D., is a physician scientist at National Institute of Health, USA. She has been involved in translational research in primary immune deficiencies (PIDs) and disorders of immune dysregulation since joining the group of Dr. Luigi Notarangelo in 2016. She assists in the development and implementation of clinical research protocols studying immunologic diseases in children and adults with PID and she conducts laboratory research aimed to characterize novel forms of monogenic PIDs and dynamics of immune reconstitution after Hematopoietic Cell Transplantation and/or gene therapy. She is particularly interested in T cell repertoire abnormalities associated with inborn errors of immunity and treatment strategies for PIDs like gene editing and gene correction. In the past 2 years she has described a novel inherited combined immunodeficiency with immune-dysregulation due to SASH3 deficiency and studied T cell repertoire perturbation in multiple newly characterized genetic disorders of the immune system including CD28 and PD1 deficiency. During the COVID-19 pandemic her research focused on virus-host interaction in individuals with life-threatening COVID-19 and multisystem inflammatory disease of children (MIS-C) and on the characterization of immunization responses to SARS-CoV-2 vaccine in patients with PIDs.
Sacco K, Castagnoli R, Vakkilainen S, Liu C, Delmonte OM, Oguz C, Kaplan IM, Alehashemi S, Burbelo PD, Bhuyan F, de Jesus AA, Dobbs K, Rosen LB, Cheng A, Shaw E, Vakkilainen MS, Pala F, Lack J, Zhang Y, Fink DL, Oikonomou V, Snow AL, Dalgard CL, Chen J, Sellers BA, Montealegre Sanchez GA, Barron K, Rey-Jurado E, Vial C, Poli MC, Licari A, Montagna D, Marseglia GL, Licciardi F, Ramenghi U, Discepolo V, Lo Vecchio A, Guarino A, Eisenstein EM, Imberti L, Sottini A, Biondi A, Mató S, Gerstbacher D, Truong M, Stack MA, Magliocco M, Bosticardo M, Kawai T, Danielson JJ, Hulett T, Askenazi M, Hu S; NIAID Immune Response to COVID Group; Chile MIS-C Group; Pavia Pediatric COVID-19 Group, Cohen JI, Su HC, Kuhns DB, Lionakis MS, Snyder TM, Holland SM, Goldbach-Mansky R, Tsang JS, Notarangelo LD. Immunopathological signatures in multisystem inflammatory syndrome in children and pediatric COVID-19. Nat Med. 2022 May;28(5):1050-1062.
Delmonte OM, Castagnoli R, Yu J, Dvorak CC, Cowan MJ, Dávila Saldaña BJ, De Ravin SS, Mamcarz E, Chang CK, Daley SR, Griffith LM, Notarangelo LD, Puck JM. Poor T-cell receptor β repertoire diversity early posttransplant for severe combined immunodeficiency predicts failure of immune reconstitution. J Allergy Clin Immunol. 2022 Mar;149(3):1113-1119.
Delmonte OM, Bergerson JRE, Burbelo PD, Durkee-Shock JR, Dobbs K, Bosticardo M, Keller MD, McDermott DH, Rao VK, Dimitrova D, Quiros-Roldan E, Imberti L, Ferrè EMN, Schmitt M, Lafeer C, Pfister J, Shaw D, Draper D, Truong M, Ulrick J, DiMaggio T, Urban A, Holland SM, Lionakis MS, Cohen JI, Ricotta EE, Notarangelo LD, Freeman AF. Antibody responses to the SARS-CoV-2 vaccine in individuals with various inborn errors of immunity. J Allergy Clin Immunol. 2021 Nov;148(5):1192-1197.
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.
Béziat V, Rapaport F, Hu J, Titeux M, Bonnet des Claustres M, Bourgey M, Griffin H, Bandet É, Ma CS, Sherkat R, Rokni-Zadeh H, Louis DM, Changi-Ashtiani M, Delmonte OM, Fukushima T, Habib T, Guennoun A, Khan T, Bender N, Rahman M, About F, Yang R, Rao G, Rouzaud C, Li J, Shearer D, Balogh K, Al Ali F, Ata M, Dabiri S, Momenilandi M, Nammour J, Alyanakian MA, Leruez-Ville M, Guenat D, Materna M, Marcot L, Vladikine N, Soret C, Vahidnezhad H, Youssefian L, Saeidian AH, Uitto J, Catherinot É, Navabi SS, Zarhrate M, Woodley DT, Jeljeli M, Abraham T, Belkaya S, Lorenzo L, Rosain J, Bayat M, Lanternier F, Lortholary O, Zakavi F, Gros P, Orth G, Abel L, Prétet JL, Fraitag S, Jouanguy E, Davis MM, Tangye SG, Notarangelo LD, Marr N, Waterboer T, Langlais D, Doorbar J, Hovnanian A, Christensen N, Bossuyt X, Shahrooei M, Casanova JL. Humans with inherited T cell CD28 deficiency are susceptible to skin papillomaviruses but are otherwise healthy. Cell. 2021 Jul 8;184(14):3812-3828.e30.
Abers MS, Delmonte OM, Ricotta EE, Fintzi J, Fink DL, de Jesus AAA, Zarember KA, Alehashemi S, Oikonomou V, Desai JV, Canna SW, Shakoory B, Dobbs K, Imberti L, Sottini A, Quiros-Roldan E, Castelli F, Rossi C, Brugnoni D, Biondi A, Bettini LR, D'Angio' M, Bonfanti P, Castagnoli R, Montagna D, Licari A, Marseglia GL, Gliniewicz EF, Shaw E, Kahle DE, Rastegar AT, Stack M, Myint-Hpu K, Levinson SL, DiNubile MJ, Chertow DW, Burbelo PD, Cohen JI, Calvo KR, Tsang JS; NIAID COVID-19 Consortium, Su HC, Gallin JI, Kuhns DB, Goldbach-Mansky R, Lionakis MS, Notarangelo LD. An immune-based biomarker signature is associated with mortality in COVID-19 patients. JCI Insight. 2021 Jan 11;6(1):e144455.
• T cell development
• T cell repertoire
• Inborn errors of immunity
• Severe combined immunodeficiency
• Combined immunodeficiency
• Immunedysregulation disorders
Soma Ghosh, Ph.D.
Major Areas of Research
- Within-host evolution of Gram-negative bacterial pathogens in the context of chronic infection and immunodeficiency
- Transcriptional and metabolic reprogramming that occurs during host adaptation
- DNA methylation and epigenetic regulation of bacterial virulence and antibiotic resistance
Program Description
Bacterial pathogens may undergo dramatic evolution in the context of chronic infection, facilitating host adaptation and the development of antibiotic resistance. Recent studies have illustrated that many general evolutionary processes can be discerned in this context, including genetic diversification of lineages with purifying selection, clonal succession events, and balanced fitness trade-offs. Dr. Ghosh’s research within the Bacterial Pathogenesis and Antimicrobial Resistance Unit (BPARU) focuses on the mechanisms of bacterial pathoadaptation that occurs in the context of persistent infection in the immunocompromised host. These questions are investigated with a combination of genomic sequencing, transcriptome analysis, DNA methylome characterization, and metabolomic profiling. This work aims to understand transcriptional and metabolic reprograming that underlies host adaptation, with implications for clinical treatment of persistent host-adapted infections.
Biography
Dr. Ghosh received her Ph.D. in 2015 from the Indian Institute of Science, Bangalore, India, where she used Systems Biology approaches to study host-pathogen interactions in the context of iron acquisition by M. tuberculosis. She joined Johns Hopkins University, Baltimore in 2015 as a post-doctoral research fellow with Dr. Tamara O’Connor in the department of Biological Chemistry. There, she studied convergent evolution in Legionella and how the combined selective pressures of residing in multiple protozoan hosts have equipped Legionella to infect mammalian hosts, including humans. Dr. Ghosh joined the BPARU as a Staff Scientist in December 2021, where she is using her combined training in computational and experimental methods to study bacterial pathogenesis.
Selected Publications
Park JM, Ghosh S, O'Connor TJ. Combinatorial selection in amoebal hosts drives the evolution of the human pathogen Legionella pneumophila. Nat Microbiol. 2020 Apr;5(4):599-609.
Ghosh S, O'Connor TJ. Beyond Paralogs: The Multiple Layers of Redundancy in Bacterial Pathogenesis. Front Cell Infect Microbiol. 2017 Nov 15;7:467.
O'Connor TJ, Zheng H, VanRheenen SM, Ghosh S, Cianciotto NP, Isberg RR. Iron Limitation Triggers Early Egress by the Intracellular Bacterial Pathogen Legionella pneumophila. Infect Immun. 2016 Jul 21;84(8):2185-2197.
Ghosh S, Chandra N, Vishveshwara S. Mechanism of Iron-Dependent Repressor (IdeR) Activation and DNA Binding: A Molecular Dynamics and Protein Structure Network Study. PLoS Comput Biol. 2015 Dec 23;11(12):e1004500.
Ghosh S, Baloni P, Mukherjee S, Anand P, Chandra N. A multi-level multi-scale approach to study essential genes in Mycobacterium tuberculosis. BMC Syst Biol. 2013 Dec 5;7:132.
Ghosh S, Prasad KV, Vishveshwara S, Chandra N. Rule-based modelling of iron homeostasis in tuberculosis. Mol Biosyst. 2011 Oct;7(10):2750-68.
Bacterial pathogens may undergo dramatic evolution in the context of chronic infection, facilitating host adaptation and the development of antibiotic resistance. Recent studies have illustrated that many general evolutionary processes can be discerned in this context, including genetic diversification of lineages with purifying selection, clonal succession events, and balanced fitness trade-offs. Dr. Ghosh’s research within the Bacterial Pathogenesis and Antimicrobial Resistance Section (BPARS) focuses on the mechanisms of bacterial pathoadaptation that occurs in the context of persistent infection in the immunocompromised host. These questions are investigated with a combination of genomic sequencing, transcriptome analysis, DNA methylome characterization, and metabolomic profiling. This work aims to understand transcriptional and metabolic reprograming that underlies host adaptation, with implications for clinical treatment of persistent host-adapted infections.
Park JM, Ghosh S, O'Connor TJ. Combinatorial selection in amoebal hosts drives the evolution of the human pathogen Legionella pneumophila. Nat Microbiol. 2020 Apr;5(4):599-609.
Ghosh S, O'Connor TJ. Beyond Paralogs: The Multiple Layers of Redundancy in Bacterial Pathogenesis. Front Cell Infect Microbiol. 2017 Nov 15;7:467.
O'Connor TJ, Zheng H, VanRheenen SM, Ghosh S, Cianciotto NP, Isberg RR. Iron Limitation Triggers Early Egress by the Intracellular Bacterial Pathogen Legionella pneumophila. Infect Immun. 2016 Jul 21;84(8):2185-2197.
Ghosh S, Chandra N, Vishveshwara S. Mechanism of Iron-Dependent Repressor (IdeR) Activation and DNA Binding: A Molecular Dynamics and Protein Structure Network Study. PLoS Comput Biol. 2015 Dec 23;11(12):e1004500.
Ghosh S, Baloni P, Mukherjee S, Anand P, Chandra N. A multi-level multi-scale approach to study essential genes in Mycobacterium tuberculosis. BMC Syst Biol. 2013 Dec 5;7:132.
Ghosh S, Prasad KV, Vishveshwara S, Chandra N. Rule-based modelling of iron homeostasis in tuberculosis. Mol Biosyst. 2011 Oct;7(10):2750-68.
- Within-host evolution of Gram-negative bacterial pathogens in the context of chronic infection and immunodeficiency
- Transcriptional and metabolic reprogramming that occurs during host adaptation
- DNA methylation and epigenetic regulation of bacterial virulence and antibiotic resistance
Ray Y. Chen
Major Areas of Research
Tuberculosis
Program Description
Clinical trials focused on diagnostics, novel treatment strategies, and treatment shortening methodologies for tuberculosis.
Biography
Dr. Chen graduated from the Medical College of Virginia/Virginia Commonwealth University in Richmond, Virginia, then trained in Internal Medicine at the Thomas Jefferson University Hospital in Philadelphia, Pennsylvania and in Infectious Diseases at the University of Alabama at Birmingham (UAB). While at UAB, he also earned a Master of Science in Public Health with a concentration in epidemiology.
Dr. Chen came to NIAID in 2003 to the Division of AIDS (DAIDS) and was based in Beijing, China for DAIDS from 2004-2012, working with Chinese investigators. In 2012, he returned to Bethesda, MD and joined the Tuberculosis Research Section in the Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research.
Selected Publications
Chen RY, Yu X, Smith B, Liu X, Gao J, Diacon AH, Dawson R, Tameris M, Zhu H, Qu Y, Zhang R, Pan S, Jin X, Goldfeder LC, Cai Y, Arora K, Wang J, Vincent J, Malherbe ST, Thienemann F, Wilkinson RJ, Walzl G, Barry CE 3rd. Radiological and functional evidence of the bronchial spread of tuberculosis: an observational analysis. Lancet Microbe. 2021 Oct;2(10):e518-e526.
Xie YL, de Jager VR, Chen RY, Dodd LE, Paripati P, Via LE, Follmann D, Wang J, Lumbard K, Lahouar S, Malherbe ST, Andrews J, Yu X, Goldfeder LC, Cai Y, Arora K, Loxton AG, Vanker N, Duvenhage M, Winter J, Song T, Walzl G, Diacon AH, Barry CE 3rd. Fourteen-day PET/CT imaging to monitor drug combination activity in treated individuals with tuberculosis. Sci Transl Med. 2021 Feb 3;13(579):eabd7618.
Lee A, Xie YL, Barry CE, Chen RY. Current and future treatments for tuberculosis. BMJ. 2020 Mar 2;368:m216.
Xie YL, Chakravorty S, Armstrong DT, Hall SL, Via LE, Song T, Yuan X, Mo X, Zhu H, Xu P, Gao Q, Lee M, Lee J, Smith LE, Chen RY, Joh JS, Cho Y, Liu X, Ruan X, Liang L, Dharan N, Cho SN, Barry CE 3rd, Ellner JJ, Dorman SE, Alland D. Evaluation of a Rapid Molecular Drug-Susceptibility Test for Tuberculosis. N Engl J Med. 2017 Sep 14;377(11):1043-1054.
Malherbe ST, Shenai S, Ronacher K, Loxton AG, Dolganov G, Kriel M, Van T, Chen RY, Warwick J, Via LE, Song T, Lee M, Schoolnik G, Tromp G, Alland D, Barry CE 3rd, Winter J, Walzl G; Catalysis TB–Biomarker Consortium, Lucas L, Spuy GV, Stanley K, Thiart L, Smith B, Du Plessis N, Beltran CG, Maasdorp E, Ellmann A, Choi H, Joh J, Dodd LE, Allwood B, Koegelenberg C, Vorster M, Griffith-Richards S. Persisting positron emission tomography lesion activity and Mycobacterium tuberculosis mRNA after tuberculosis cure. Nat Med. 2016 Oct;22(10):1094-1100.
Chen RY, Dodd LE, Lee M, Paripati P, Hammoud DA, Mountz JM, Jeon D, Zia N, Zahiri H, Coleman MT, Carroll MW, Lee JD, Jeong YJ, Herscovitch P, Lahouar S, Tartakovsky M, Rosenthal A, Somaiyya S, Lee S, Goldfeder LC, Cai Y, Via LE, Park SK, Cho SN, Barry CE 3rd. PET/CT imaging correlates with treatment outcome in patients with multidrug-resistant tuberculosis. Sci Transl Med. 2014 Dec 3;6(265):265ra166.
Clinical trials focused on diagnostics, novel treatment strategies, and treatment shortening methodologies for tuberculosis.
Chen RY, Yu X, Smith B, Liu X, Gao J, Diacon AH, Dawson R, Tameris M, Zhu H, Qu Y, Zhang R, Pan S, Jin X, Goldfeder LC, Cai Y, Arora K, Wang J, Vincent J, Malherbe ST, Thienemann F, Wilkinson RJ, Walzl G, Barry CE 3rd. Radiological and functional evidence of the bronchial spread of tuberculosis: an observational analysis. Lancet Microbe. 2021 Oct;2(10):e518-e526.
Xie YL, de Jager VR, Chen RY, Dodd LE, Paripati P, Via LE, Follmann D, Wang J, Lumbard K, Lahouar S, Malherbe ST, Andrews J, Yu X, Goldfeder LC, Cai Y, Arora K, Loxton AG, Vanker N, Duvenhage M, Winter J, Song T, Walzl G, Diacon AH, Barry CE 3rd. Fourteen-day PET/CT imaging to monitor drug combination activity in treated individuals with tuberculosis. Sci Transl Med. 2021 Feb 3;13(579):eabd7618.
Lee A, Xie YL, Barry CE, Chen RY. Current and future treatments for tuberculosis. BMJ. 2020 Mar 2;368:m216.
Xie YL, Chakravorty S, Armstrong DT, Hall SL, Via LE, Song T, Yuan X, Mo X, Zhu H, Xu P, Gao Q, Lee M, Lee J, Smith LE, Chen RY, Joh JS, Cho Y, Liu X, Ruan X, Liang L, Dharan N, Cho SN, Barry CE 3rd, Ellner JJ, Dorman SE, Alland D. Evaluation of a Rapid Molecular Drug-Susceptibility Test for Tuberculosis. N Engl J Med. 2017 Sep 14;377(11):1043-1054.
Malherbe ST, Shenai S, Ronacher K, Loxton AG, Dolganov G, Kriel M, Van T, Chen RY, Warwick J, Via LE, Song T, Lee M, Schoolnik G, Tromp G, Alland D, Barry CE 3rd, Winter J, Walzl G; Catalysis TB–Biomarker Consortium, Lucas L, Spuy GV, Stanley K, Thiart L, Smith B, Du Plessis N, Beltran CG, Maasdorp E, Ellmann A, Choi H, Joh J, Dodd LE, Allwood B, Koegelenberg C, Vorster M, Griffith-Richards S. Persisting positron emission tomography lesion activity and Mycobacterium tuberculosis mRNA after tuberculosis cure. Nat Med. 2016 Oct;22(10):1094-1100.
Chen RY, Dodd LE, Lee M, Paripati P, Hammoud DA, Mountz JM, Jeon D, Zia N, Zahiri H, Coleman MT, Carroll MW, Lee JD, Jeong YJ, Herscovitch P, Lahouar S, Tartakovsky M, Rosenthal A, Somaiyya S, Lee S, Goldfeder LC, Cai Y, Via LE, Park SK, Cho SN, Barry CE 3rd. PET/CT imaging correlates with treatment outcome in patients with multidrug-resistant tuberculosis. Sci Transl Med. 2014 Dec 3;6(265):265ra166.
- Tuberculosis