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

• Grant number: 13/50303-0
• Support Opportunities: Regular Research Grants
• Start date: November 01, 2013
• End date: October 31, 2016
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Agreement: 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

Abstract

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)

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, DEC 15 2017. (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, OCT 2016. (13/50303-0)