We are working on the identification, description, and treatment of congenital and acquired syndromes of increased susceptibility to mycobacterial and intracellular fungal infections. The syndromes in which we are interested primarily affect the phagocytes, and are most apparent in the increased susceptibility to nontuberculous mycobacteria. These organisms are thought to be important pathogens only in the immunocompromised host. Therefore, we have sought to identify patients without previously recognized forms of immunocompromise who have these infections and then determine the nature of their susceptibility. In this way we have identified and characterized the pathways involved in the control of mycobacteria and other intracellular pathogens, such as Salmonella, histoplasmosis, and coccidioidomycosis, and cryptococcosis as well as nontuberculous mycobacteria. The abnormalities we have already identified center around macrophage/lymphocyte interactions leading to the production of or response to interferon gamma, IL-12, and tumor necrosis factor. In addition, the pathways regulating the response to tumor necrosis factor overlap with the interferon gamma signaling pathways and have been shown to be lesioned in patients with these infections. The study of these """"""""experiments of nature"""""""" highlights the critical role of the macrophage/ lymphocyte interaction in control of mycobacteria and other intracellular pathogens, including fungi. These observations have led us to explore cytokine therapies and cytokine modifying therapies that may have broader applications to the treatment of tuberculosis. Over the last year we have continued our focus on the importance of the regulation of inflammatory genes in mycobacterial infections through the study of patients with extrapulmonary fungi. We have identified abnormalities in cytokine receptors and signaling in those with histoplasmosis and coccidioidomycosis as well as as mycobacteria. We have also focused on the syndrome of monocytopenia and mycobacterial disease (MonoMAC), which also predisposes to myelodysplasia and malignancy.

Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Zip Code
Moutsopoulos, Niki M; Zerbe, Christa S; Wild, Teresa et al. (2017) Interleukin-12 and Interleukin-23 Blockade in Leukocyte Adhesion Deficiency Type 1. N Engl J Med 376:1141-1146
Fleshner, M; Olivier, K N; Shaw, P A et al. (2016) Mortality among patients with pulmonary non-tuberculous mycobacteria disease. Int J Tuberc Lung Dis 20:582-7
Lawrence, Monica G; Leiding, Jennifer W; Lyons, Jonathan J et al. (2016) GATA3 haploinsufficiency does not block allergic sensitization or atopic disease. J Allergy Clin Immunol 137:627-629.e2
Zerbe, Christa S; Marciano, Beatriz E; Katial, Rohit K et al. (2016) Progressive Multifocal Leukoencephalopathy in Primary Immune Deficiencies: Stat1 Gain of Function and Review of the Literature. Clin Infect Dis 62:986-94
Milligan, Ki Lee; Mann, Daphne; Rump, Amy et al. (2016) Complete Myeloperoxidase Deficiency: Beware the ""False-Positive"" Dihydrorhodamine Oxidation. J Pediatr 176:204-6
Ku, Cheng-Lung; Lin, Chia-Hao; Chang, Su-Wei et al. (2016) Anti-IFN-? autoantibodies are strongly associated with HLA-DR*15:02/16:02 and HLA-DQ*05:01/05:02 across Southeast Asia. J Allergy Clin Immunol 137:945-8.e8
Crescente, Vincenzo; Holland, Sinead M; Kashyap, Sapna et al. (2016) Identification of novel members of the bacterial azoreductase family in Pseudomonas aeruginosa. Biochem J 473:549-58
Myles, Ian A; Zhao, Ming; Nardone, Glenn et al. (2016) CD8+ T cells produce a dialyzable antigen-specific activator of dendritic cells. J Leukoc Biol :
Gupta, Sarthak; Tatouli, Ioanna P; Rosen, Lindsey B et al. (2016) Distinct Functions of Autoantibodies Against Interferon in Systemic Lupus Erythematosus: A Comprehensive Analysis of Anticytokine Autoantibodies in Common Rheumatic Diseases. Arthritis Rheumatol 68:1677-87
Cohen, Jeffrey I; Dropulic, Lesia; Hsu, Amy P et al. (2016) Association of GATA2 Deficiency With Severe Primary Epstein-Barr Virus (EBV) Infection and EBV-associated Cancers. Clin Infect Dis 63:41-7

Showing the most recent 10 out of 143 publications