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.

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Esteve-Sole, Ana; Sánchez-Dávila, Suly P; Deyà-Martínez, Angela et al. (2018) Severe BCG-osis Misdiagnosed as Multidrug-Resistant Tuberculosis in an IL-12R?1-Deficient Peruvian Girl. J Clin Immunol 38:712-716
Bousfiha, Aziz; Jeddane, Leïla; Picard, Capucine et al. (2018) The 2017 IUIS Phenotypic Classification for Primary Immunodeficiencies. J Clin Immunol 38:129-143
Henrickson, Sarah E; Walter, Jolan E; Quinn, Colin et al. (2018) Adult-Onset Myopathy in a Patient with Hypomorphic RAG2 Mutations and Combined Immune Deficiency. J Clin Immunol 38:642-645
McReynolds, Lisa J; Calvo, Katherine R; Holland, Steven M (2018) Germline GATA2 Mutation and Bone Marrow Failure. Hematol Oncol Clin North Am 32:713-728
Hsu, Amy P; Zerbe, Christa S; Foruraghi, Ladan et al. (2018) IKBKG (NEMO) 5' Untranslated Splice Mutations Lead to Severe, Chronic Disseminated Mycobacterial Infections. Clin Infect Dis 67:456-459
Boutboul, David; Kuehn, Hye Sun; Van de Wyngaert, Zoé et al. (2018) Dominant-negative IKZF1 mutations cause a T, B, and myeloid cell combined immunodeficiency. J Clin Invest 128:3071-3087
Picard, Capucine; Bobby Gaspar, H; Al-Herz, Waleed et al. (2018) International Union of Immunological Societies: 2017 Primary Immunodeficiency Diseases Committee Report on Inborn Errors of Immunity. J Clin Immunol 38:96-128
Feriani, Luigi; Juenet, Maya; Fowler, Cedar J et al. (2017) Assessing the Collective Dynamics of Motile Cilia in Cultures of Human Airway Cells by Multiscale DDM. Biophys J 113:109-119
Holland, Steven M; Pierce, Virginia M; Shailam, Randheer et al. (2017) Case 28-2017. A 13-Month-Old Girl with Pneumonia and a 33-Year-Old Woman with Hip Pain. N Engl J Med 377:1077-1091
Fisher, Kevin E; Hsu, Amy P; Williams, Christopher L et al. (2017) Somatic mutations in children with GATA2-associated myelodysplastic syndrome who lack other features of GATA2 deficiency. Blood Adv 1:443-448

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