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

Detalhes bibliográficos
Autor(a) principal: Schimke, Lena F.
Data de Publicação: 2017
Outros Autores: Hibbard, James, Martinez-Barricarte, Ruben, Khan, Taj Ali, Cavalcante, Ricardo de Souza [UNESP], Oliveira Junior, Edgar Borges de, Franca, Tabata Takahashi, Iqbal, Asif, Yamamoto, Guilherme, Arslanian, Christina, Feriotti, Claudia, Costa, Tania Alves, Bustamante, Jacinta, Boisson-Dupuis, Stephanie, Casanova, Jean-Laurent, Marzagao Barbuto, Jose Alexandre, Zatz, Mayana, Mendes, Rinaldo Poncio [UNESP], Garcia Calich, Vera Lucia, Ochs, Hans D., Torgerson, Troy R., Cabral-Marques, Otavio, Condino-Neto, Antonio
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Institucional da UNESP
Texto Completo: http://dx.doi.org/10.1093/infdis/jix522
http://hdl.handle.net/11449/163664
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.
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spelling Paracoccidioidomycosis Associated With a Heterozygous STAT4 Mutation and Impaired IFN-gamma ImmunitySTAT4 deficiencyprimary immunodeficiencyIL-12/IFN-gamma axisparacoccidioidomycosisBackground. 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.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Univ Sao Paulo, Dept Immunol, Sao Paulo, BrazilUniv Lubeck, Dept Rheumatol & Clin Immunol, Lubeck, GermanyUniv Washington, Sch Med, Dept Pediat, Seattle, WA 98195 USASeattle Childrens Res Inst, Seattle, WA USARockefeller Univ, St Giles Lab Human Genet Infect Dis, 1230 York Ave, New York, NY 10021 USASao Paulo State Univ, Botucatu Med Sch, Trop Dis Area, Sao Paulo, BrazilButantan Inst, Lab Biochem & Biophys, Sao Paulo, BrazilUniv Sao Paulo, Human Genome & Stem Cell Res Ctr, Sao Paulo, BrazilParis Descartes Univ, Imagine Inst, Paris, FranceNecker Hosp Sick Children, Lab Human Genet Infect Dis, Paris, FranceNecker Hosp Sick Children, Ctr Study Primary Immunodeficiencies, Paris, FranceNecker Hosp Sick Children, Pediat Hematol Immunol Unit, Paris, FranceRockefeller Univ, Howard Hughes Med Inst, New York, NY 10021 USAUniv Sao Paulo, Inst Trop Med, Sao Paulo, BrazilSao Paulo State Univ, Botucatu Med Sch, Trop Dis Area, Sao Paulo, BrazilFAPESP: 2011/2507-1FAPESP: 2/51745-3FAPESP: 13/50303-0Oxford Univ Press IncUniversidade de São Paulo (USP)Univ LubeckUniv WashingtonSeattle Childrens Res InstRockefeller UnivUniversidade Estadual Paulista (Unesp)Butantan InstNecker Hosp Sick ChildrenSchimke, Lena F.Hibbard, JamesMartinez-Barricarte, RubenKhan, Taj AliCavalcante, Ricardo de Souza [UNESP]Oliveira Junior, Edgar Borges deFranca, Tabata TakahashiIqbal, AsifYamamoto, GuilhermeArslanian, ChristinaFeriotti, ClaudiaCosta, Tania AlvesBustamante, JacintaBoisson-Dupuis, StephanieCasanova, Jean-LaurentMarzagao Barbuto, Jose AlexandreZatz, MayanaMendes, Rinaldo Poncio [UNESP]Garcia Calich, Vera LuciaOchs, Hans D.Torgerson, Troy R.Cabral-Marques, OtavioCondino-Neto, Antonio2018-11-26T17:44:29Z2018-11-26T17:44:29Z2017-12-15info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article1623-1634application/pdfhttp://dx.doi.org/10.1093/infdis/jix522Journal Of Infectious Diseases. Cary: Oxford Univ Press Inc, v. 216, n. 12, p. 1623-1634, 2017.0022-1899http://hdl.handle.net/11449/16366410.1093/infdis/jix522WOS:000418720000017WOS000418720000017.pdfWeb of Sciencereponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengJournal Of Infectious Diseases3,302info:eu-repo/semantics/openAccess2024-08-15T15:22:48Zoai:repositorio.unesp.br:11449/163664Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462024-08-15T15:22:48Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false
dc.title.none.fl_str_mv Paracoccidioidomycosis Associated With a Heterozygous STAT4 Mutation and Impaired IFN-gamma Immunity
title Paracoccidioidomycosis Associated With a Heterozygous STAT4 Mutation and Impaired IFN-gamma Immunity
spellingShingle Paracoccidioidomycosis Associated With a Heterozygous STAT4 Mutation and Impaired IFN-gamma Immunity
Schimke, Lena F.
STAT4 deficiency
primary immunodeficiency
IL-12/IFN-gamma axis
paracoccidioidomycosis
title_short Paracoccidioidomycosis Associated With a Heterozygous STAT4 Mutation and Impaired IFN-gamma Immunity
title_full Paracoccidioidomycosis Associated With a Heterozygous STAT4 Mutation and Impaired IFN-gamma Immunity
title_fullStr Paracoccidioidomycosis Associated With a Heterozygous STAT4 Mutation and Impaired IFN-gamma Immunity
title_full_unstemmed Paracoccidioidomycosis Associated With a Heterozygous STAT4 Mutation and Impaired IFN-gamma Immunity
title_sort Paracoccidioidomycosis Associated With a Heterozygous STAT4 Mutation and Impaired IFN-gamma Immunity
author Schimke, Lena F.
author_facet Schimke, Lena F.
Hibbard, James
Martinez-Barricarte, Ruben
Khan, Taj Ali
Cavalcante, Ricardo de Souza [UNESP]
Oliveira Junior, Edgar Borges de
Franca, Tabata Takahashi
Iqbal, Asif
Yamamoto, Guilherme
Arslanian, Christina
Feriotti, Claudia
Costa, Tania Alves
Bustamante, Jacinta
Boisson-Dupuis, Stephanie
Casanova, Jean-Laurent
Marzagao Barbuto, Jose Alexandre
Zatz, Mayana
Mendes, Rinaldo Poncio [UNESP]
Garcia Calich, Vera Lucia
Ochs, Hans D.
Torgerson, Troy R.
Cabral-Marques, Otavio
Condino-Neto, Antonio
author_role author
author2 Hibbard, James
Martinez-Barricarte, Ruben
Khan, Taj Ali
Cavalcante, Ricardo de Souza [UNESP]
Oliveira Junior, Edgar Borges de
Franca, Tabata Takahashi
Iqbal, Asif
Yamamoto, Guilherme
Arslanian, Christina
Feriotti, Claudia
Costa, Tania Alves
Bustamante, Jacinta
Boisson-Dupuis, Stephanie
Casanova, Jean-Laurent
Marzagao Barbuto, Jose Alexandre
Zatz, Mayana
Mendes, Rinaldo Poncio [UNESP]
Garcia Calich, Vera Lucia
Ochs, Hans D.
Torgerson, Troy R.
Cabral-Marques, Otavio
Condino-Neto, Antonio
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universidade de São Paulo (USP)
Univ Lubeck
Univ Washington
Seattle Childrens Res Inst
Rockefeller Univ
Universidade Estadual Paulista (Unesp)
Butantan Inst
Necker Hosp Sick Children
dc.contributor.author.fl_str_mv Schimke, Lena F.
Hibbard, James
Martinez-Barricarte, Ruben
Khan, Taj Ali
Cavalcante, Ricardo de Souza [UNESP]
Oliveira Junior, Edgar Borges de
Franca, Tabata Takahashi
Iqbal, Asif
Yamamoto, Guilherme
Arslanian, Christina
Feriotti, Claudia
Costa, Tania Alves
Bustamante, Jacinta
Boisson-Dupuis, Stephanie
Casanova, Jean-Laurent
Marzagao Barbuto, Jose Alexandre
Zatz, Mayana
Mendes, Rinaldo Poncio [UNESP]
Garcia Calich, Vera Lucia
Ochs, Hans D.
Torgerson, Troy R.
Cabral-Marques, Otavio
Condino-Neto, Antonio
dc.subject.por.fl_str_mv STAT4 deficiency
primary immunodeficiency
IL-12/IFN-gamma axis
paracoccidioidomycosis
topic STAT4 deficiency
primary immunodeficiency
IL-12/IFN-gamma axis
paracoccidioidomycosis
description 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.
publishDate 2017
dc.date.none.fl_str_mv 2017-12-15
2018-11-26T17:44:29Z
2018-11-26T17:44:29Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://dx.doi.org/10.1093/infdis/jix522
Journal Of Infectious Diseases. Cary: Oxford Univ Press Inc, v. 216, n. 12, p. 1623-1634, 2017.
0022-1899
http://hdl.handle.net/11449/163664
10.1093/infdis/jix522
WOS:000418720000017
WOS000418720000017.pdf
url http://dx.doi.org/10.1093/infdis/jix522
http://hdl.handle.net/11449/163664
identifier_str_mv Journal Of Infectious Diseases. Cary: Oxford Univ Press Inc, v. 216, n. 12, p. 1623-1634, 2017.
0022-1899
10.1093/infdis/jix522
WOS:000418720000017
WOS000418720000017.pdf
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv Journal Of Infectious Diseases
3,302
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 1623-1634
application/pdf
dc.publisher.none.fl_str_mv Oxford Univ Press Inc
publisher.none.fl_str_mv Oxford Univ Press Inc
dc.source.none.fl_str_mv Web of Science
reponame:Repositório Institucional da UNESP
instname:Universidade Estadual Paulista (UNESP)
instacron:UNESP
instname_str Universidade Estadual Paulista (UNESP)
instacron_str UNESP
institution UNESP
reponame_str Repositório Institucional da UNESP
collection Repositório Institucional da UNESP
repository.name.fl_str_mv Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)
repository.mail.fl_str_mv
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