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Human anti-tuberculous IFN-y-dependent immunity is mediated by the phagocytic NADPH oxidase

Grant number: 13/50303-0
Support Opportunities:Regular Research Grants
Duration: November 01, 2013 - October 31, 2016
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Convênio/Acordo: ANR - Blanc
Principal Investigator:Antonio Condino Neto
Grantee:Antonio Condino Neto
Principal researcher abroad: Jacinta Bustamante
Institution abroad: Université Paris Descartes - Paris 5, France
Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil


We hypothesize that the constitutive expression of one or more NADPH oxidase components and the function of the entire NADPH oxidase complex is dependent on IFN-gamma in human mocrophages and probably in dendritic cells. Thus, inborn errors of IFN-gamma responses in patients with Mendelian Susceptibility to Mycobacterial Infections (MSMD) with IFNGR deficiency should result in defective expression of one or more components of the NADPH oxidase system in macrophages, thereby resulting impaired respiratory burst activity in these cells and susceptibility to BCG and M. tuberculosis in these MSMD patients. Normal respiratory burst activity in granulocytes and monocytes from these IFNGR-deficient MSMD patients should protect against other bacteria and fungi, accounting for the lack of infections typically obsrved in CGD patients. Therefore, the principal objective of the present appfication is to identify the key anti-mycobacterial target genes downstream the IFNGR pathway, inciuding one or more genes enconding compents ofthe NADPH oxidase, at least for immunity against BCG and M. tuberculosis. In order to test this hypothesis. we will test MSMD patients' primary cell (such as granulocytes, monocytes and macrophages), EBV-transformed B cetls, monocyte-derived macrophages (MDMs), and dendritic cells. Our project is highly innovative and supported by promising preliminary evidence. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
SCHIMKE, LENA F.; HIBBARD, JAMES; MARTINEZ-BARRICARTE, RUBEN; KHAN, TAJ ALI; CAVALCANTE, RICARDO DE SOUZA; DE OLIVEIRA JUNIOR, EDGAR BORGES; FRANCA, TABATA TAKAHASHI; IQBAL, ASIF; YAMAMOTO, GUILHERME; ARSLANIAN, CHRISTINA; et al. Paracoccidioidomycosis Associated With a Heterozygous STAT4 Mutation and Impaired IFN-gamma Immunity. Journal of Infectious Diseases, v. 216, n. 12, p. 1623-1634, . (13/50303-0)
OLIVEIRA-CORTEZ, A.; MELO, A. C.; CHAVES, V. E.; CONDINO-NETO, A.; CAMARGOS, P.. Do HLA class II genes protect against pulmonary tuberculosis? A systematic review and meta-analysis. EUROPEAN JOURNAL OF CLINICAL MICROBIOLOGY & INFECTIOUS DISEASES, v. 35, n. 10, p. 1567-1580, . (13/50303-0)

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