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

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dc.contributor.authorSchimke, Lena F.
dc.contributor.authorHibbard, James
dc.contributor.authorMartinez-Barricarte, Ruben
dc.contributor.authorKhan, Taj Ali
dc.contributor.authorCavalcante, Ricardo de Souza [UNESP]
dc.contributor.authorOliveira Junior, Edgar Borges de
dc.contributor.authorFranca, Tabata Takahashi
dc.contributor.authorIqbal, Asif
dc.contributor.authorYamamoto, Guilherme
dc.contributor.authorArslanian, Christina
dc.contributor.authorFeriotti, Claudia
dc.contributor.authorCosta, Tania Alves
dc.contributor.authorBustamante, Jacinta
dc.contributor.authorBoisson-Dupuis, Stephanie
dc.contributor.authorCasanova, Jean-Laurent
dc.contributor.authorMarzagao Barbuto, Jose Alexandre
dc.contributor.authorZatz, Mayana
dc.contributor.authorMendes, Rinaldo Poncio [UNESP]
dc.contributor.authorGarcia Calich, Vera Lucia
dc.contributor.authorOchs, Hans D.
dc.contributor.authorTorgerson, Troy R.
dc.contributor.authorCabral-Marques, Otavio
dc.contributor.authorCondino-Neto, Antonio
dc.contributor.institutionUniversidade de São Paulo (USP)
dc.contributor.institutionUniv Lubeck
dc.contributor.institutionUniv Washington
dc.contributor.institutionSeattle Childrens Res Inst
dc.contributor.institutionRockefeller Univ
dc.contributor.institutionUniversidade Estadual Paulista (Unesp)
dc.contributor.institutionButantan Inst
dc.contributor.institutionNecker Hosp Sick Children
dc.date.accessioned2018-11-26T17:44:29Z
dc.date.available2018-11-26T17:44:29Z
dc.date.issued2017-12-15
dc.description.abstractBackground. 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.en
dc.description.affiliationUniv Sao Paulo, Dept Immunol, Sao Paulo, Brazil
dc.description.affiliationUniv Lubeck, Dept Rheumatol & Clin Immunol, Lubeck, Germany
dc.description.affiliationUniv Washington, Sch Med, Dept Pediat, Seattle, WA 98195 USA
dc.description.affiliationSeattle Childrens Res Inst, Seattle, WA USA
dc.description.affiliationRockefeller Univ, St Giles Lab Human Genet Infect Dis, 1230 York Ave, New York, NY 10021 USA
dc.description.affiliationSao Paulo State Univ, Botucatu Med Sch, Trop Dis Area, Sao Paulo, Brazil
dc.description.affiliationButantan Inst, Lab Biochem & Biophys, Sao Paulo, Brazil
dc.description.affiliationUniv Sao Paulo, Human Genome & Stem Cell Res Ctr, Sao Paulo, Brazil
dc.description.affiliationParis Descartes Univ, Imagine Inst, Paris, France
dc.description.affiliationNecker Hosp Sick Children, Lab Human Genet Infect Dis, Paris, France
dc.description.affiliationNecker Hosp Sick Children, Ctr Study Primary Immunodeficiencies, Paris, France
dc.description.affiliationNecker Hosp Sick Children, Pediat Hematol Immunol Unit, Paris, France
dc.description.affiliationRockefeller Univ, Howard Hughes Med Inst, New York, NY 10021 USA
dc.description.affiliationUniv Sao Paulo, Inst Trop Med, Sao Paulo, Brazil
dc.description.affiliationUnespSao Paulo State Univ, Botucatu Med Sch, Trop Dis Area, Sao Paulo, Brazil
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.description.sponsorshipConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
dc.description.sponsorshipIdFAPESP: 2011/2507-1
dc.description.sponsorshipIdFAPESP: 2/51745-3
dc.description.sponsorshipIdFAPESP: 13/50303-0
dc.format.extent1623-1634
dc.identifierhttp://dx.doi.org/10.1093/infdis/jix522
dc.identifier.citationJournal Of Infectious Diseases. Cary: Oxford Univ Press Inc, v. 216, n. 12, p. 1623-1634, 2017.
dc.identifier.doi10.1093/infdis/jix522
dc.identifier.fileWOS000418720000017.pdf
dc.identifier.issn0022-1899
dc.identifier.urihttp://hdl.handle.net/11449/163664
dc.identifier.wosWOS:000418720000017
dc.language.isoeng
dc.publisherOxford Univ Press Inc
dc.relation.ispartofJournal Of Infectious Diseases
dc.relation.ispartofsjr3,302
dc.rights.accessRightsAcesso aberto
dc.sourceWeb of Science
dc.subjectSTAT4 deficiency
dc.subjectprimary immunodeficiency
dc.subjectIL-12/IFN-gamma axis
dc.subjectparacoccidioidomycosis
dc.titleParacoccidioidomycosis Associated With a Heterozygous STAT4 Mutation and Impaired IFN-gamma Immunityen
dc.typeArtigo
dcterms.licensehttp://www.oxfordjournals.org/access_purchase/self-archiving_policyb.html
dcterms.rightsHolderOxford Univ Press Inc
unesp.author.orcid0000-0002-3439-2482[13]
unesp.author.orcid0000-0002-7115-116X[14]
unesp.author.orcid0000-0003-3970-8025[17]

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