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, 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 is due to mutations in GATA2 and also predisposes to myelodysplasia and malignancy.

Project Start
Project End
Budget Start
Budget End
Support Year
22
Fiscal Year
2013
Total Cost
$2,042,766
Indirect Cost
City
State
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Chien, Wade Wei-De; Leiding, Jennifer W; Hsu, Amy P et al. (2014) Auditory and vestibular phenotypes associated with GATA3 mutation. Otol Neurotol 35:577-81
Haverkamp, Margje H; Marciano, Beatriz E; Frucht, David M et al. (2014) Correlating interleukin-12 stimulated interferon-? production and the absence of ectodermal dysplasia and anhidrosis (EDA) in patients with mutations in NF-?B essential modulator (NEMO). J Clin Immunol 34:436-43
Muszynski, Melissa A; Zerbe, Christa S; Holland, Steven M et al. (2014) A woman with warts, leg swelling, and deafness. J Am Acad Dermatol 71:577-80
O'Connell, Elise; Rosen, Lindsey B; LaRue, Richard W et al. (2014) The first US domestic report of disseminated Mycobacterium avium complex and anti-interferon-? autoantibodies. J Clin Immunol 34:928-32
Tettelin, Hervé; Davidson, Rebecca M; Agrawal, Sonia et al. (2014) High-level relatedness among Mycobacterium abscessus subsp. massiliense strains from widely separated outbreaks. Emerg Infect Dis 20:364-71
Simhadri, Venkateswara R; Mariano, John L; Zenarruzabeitia, Olatz et al. (2014) Intact IL-12 signaling is necessary for the generation of human natural killer cells with enhanced effector function after restimulation. J Allergy Clin Immunol 134:1190-3.e1
West, E S; Kingsbery, M Y; Mintz, E M et al. (2014) Generalized verrucosis in a patient with GATA2 deficiency. Br J Dermatol 170:1182-6
Haverkamp, M H; van de Vosse, E; Goldbach-Mansky, R et al. (2014) Impaired cytokine responses in patients with cryopyrin-associated periodic syndrome (CAPS). Clin Exp Immunol 177:720-31
Saijo, Tomomi; Chen, Jianghan; Chen, Sharon C-A et al. (2014) Anti-granulocyte-macrophage colony-stimulating factor autoantibodies are a risk factor for central nervous system infection by Cryptococcus gattii in otherwise immunocompetent patients. MBio 5:e00912-14
Rose, David M; Atkins, Jane; Holland, Steven M et al. (2014) A novel mutation in IFN-? receptor 1 presenting as multisystem Mycobacterium intracellulare infection. J Allergy Clin Immunol 133:591-2

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