Paracoccidioidomycosis Associated With a Heterozygous STAT4 Mutation and Impaired IFN-gamma Immunity

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Schimke, Lena F. ^{[1, 2]} ; Hibbard, James ^{[3, 4]} ; Martinez-Barricarte, Ruben ^[5] ; Khan, Taj Ali ^[1] ; Cavalcante, Ricardo de Souza ^[6] ; de Oliveira Junior, Edgar Borges ^[1] ; Franca, Tabata Takahashi ^[1] ; Iqbal, Asif ^[7] ; Yamamoto, Guilherme ^[8] ; Arslanian, Christina ^[1] ; Feriotti, Claudia ^[1] ; Costa, Tania Alves ^[1] ; Bustamante, Jacinta ^{[9, 5, 10, 11]} ; Boisson-Dupuis, Stephanie ^{[9, 5, 10]} ; Casanova, Jean-Laurent ^{[12, 9, 13, 5, 10]} ; Marzagao Barbuto, Jose Alexandre ^[1] ; Zatz, Mayana ^[8] ; Mendes, Rinaldo Poncio ^[6] ; Garcia Calich, Vera Lucia ^[1] ; Ochs, Hans D. ^{[3, 4]} ; Torgerson, Troy R. ^{[3, 4]} ; Cabral-Marques, Otavio ^{[1, 2]} ; Condino-Neto, Antonio ^{[14, 1]}

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^[1] Univ Sao Paulo, Dept Immunol, Sao Paulo - Brazil

^[2] Univ Lubeck, Dept Rheumatol & Clin Immunol, Lubeck - Germany

^[3] Univ Washington, Sch Med, Dept Pediat, Seattle, WA 98195 - USA

^[4] Seattle Childrens Res Inst, Seattle, WA - USA

^[5] Rockefeller Univ, St Giles Lab Human Genet Infect Dis, 1230 York Ave, New York, NY 10021 - USA

^[6] Sao Paulo State Univ, Botucatu Med Sch, Trop Dis Area, Sao Paulo - Brazil

^[7] Butantan Inst, Lab Biochem & Biophys, Sao Paulo - Brazil

^[8] Univ Sao Paulo, Human Genome & Stem Cell Res Ctr, Sao Paulo - Brazil

^[9] Paris Descartes Univ, Imagine Inst, Paris - France

^[10] Necker Hosp Sick Children, Lab Human Genet Infect Dis, Paris - France

^[11] Necker Hosp Sick Children, Ctr Study Primary Immunodeficiencies, Paris - France

^[12] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10021 - USA

^[13] Necker Hosp Sick Children, Pediat Hematol Immunol Unit, Paris - France

^[14] Univ Sao Paulo, Inst Trop Med, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Journal of Infectious Diseases; v. 216, n. 12, p. 1623-1634, DEC 15 2017.
• Citações Web of Science: 6

Resumo

Background. Mutations in genes affecting interferon-gamma (IFN-gamma) immunity have contributed to understand the role of IFN-gamma in protection against intracellular pathogens. However, inborn errors in STAT4, which controls interleukin-12 (IL-12) responses, have not yet been reported. Our objective was to determine the genetic defect in a family with a history of paracoccidioidomycosis. Methods. Genetic analysis was performed by whole-exome sequencing and Sanger sequencing. STAT4 phosphorylation (pSTAT4) and translocation to the nucleus, IFN-gamma release by patient lymphocytes, and microbicidal activity of patient monocytes/macrophages were assessed. The effect on STAT4 function was evaluated by site-directed mutagenesis using a lymphoblastoid B cell line (B-LCL) and U3A cells. Results. A heterozygous missense mutation, c.1952 A > T (p.E651V) in STAT4 was identified in the index patient and her father. Patient's and father's lymphocytes showed reduced pSTAT4, nuclear translocation, and impaired IFN-gamma production. Mutant B-LCL and U3A cells also displayed reduced pSTAT4. Patient's and father's peripheral blood mononuclear cells and macrophages demonstrated impaired fungicidal activity compared with those from healthy controls that improved in the presence of recombinant human IFN-gamma, but not rhIL-12. Conclusion. Our data suggest autosomal dominant STAT4 deficiency as a novel inborn error of IL-12-dependent IFN-gamma immunity associated with susceptibility to paracoccidioidomycosis. (AU)

• Processo FAPESP: 13/50303-0 - A imunidade anti-tuberculose em humanos dependentes de IFN-y e mediada pela NADPH oxidase dos fagócitos
• Beneficiário: Antonio Condino Neto
• Modalidade de apoio: Auxílio à Pesquisa - Regular