Signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations and disseminated coccidioidomycosis and histoplasmosis

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• 作者：Elizabeth P. Sampaio ; MD ; PhD^a ; ^b ; Amy P. Hsu ; BA^a ; Joseph Pechacek ; BA^a ; Hannelore I. Bax ; MD^a ; ^c ; Dalton L. Dias ; BA^a ; Michelle L. Paulson ; MD^d ; Prabha Chandrasekaran ; PhD^a ; Lindsey B. Rosen ; BS^a ; Daniel S. Carvalho ; PhD^a ; ^b ; Li Ding ; MD^a ; Donald C. Vinh ; MD^e ; Sarah K. Browne ; MD^a ; Shrimati Datta ; PhD^f ; Joshua D. Milner ; MD^f ; Douglas B. Kuhns ; PhD^g ; Debra A. Long Priel ; BS^g ; Mohammed A. Sadat ; MD^h ; Michael Shiloh ; MD ; PhDⁱ ; Brendan De Marco ; MDⁱ ; Michael Alvares ; MD^j ; Jason W. Gillman ; MDⁱ ; Vivek Ramarathnam ; MDⁱ ; Maite de la Morena ; MD^j ; Liliana Bezrodnik ; MD^k ; Ileana Moreira ; MD^k ; Gulbu Uzel ; MD^a ; Daniel Johnson ; MD^l ; Christine Spalding ; RN^a ; Christa S. Zerbe ; MD^a ; Henry Wiley ; MD^m ; David E. Greenberg ; MDⁱ ; Susan E. Hoover ; MD ; PhDⁿ ; Sergio D. Rosenzweig ; MD ; PhD^h ; ^o ; John N. Galgiani ; MDⁿ ; Steven M. Holland ; MD^a ; ^smh@nih.gov
• 关键词：Signal transducer and activator of transcription 1 ; IFN-¦Ã ; progressive multifocal leukoencephalopathy ; Histoplasma capsulatum ; Coccidioides immitis ; thrush
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2013
• 出版时间：June, 2013
• 年：2013
• 卷：131
• 期：6
• 页码：1624-1634.e17
• 全文大小：6000 K

文摘

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Background

Impaired signaling in the IFN-¦Ã/IL-12 pathway causes susceptibility to severe disseminated infections with mycobacteria and dimorphic yeasts. Dominant gain-of-function mutations in signal transducer and activator of transcription 1 (STAT1) have been associated with chronic mucocutaneous candidiasis.

Objective

We sought to identify the molecular defect in patients with disseminated dimorphic yeast infections.

Methods

PBMCs, EBV-transformed B cells, and transfected U3A cell lines were studied for IFN-¦Ã/IL-12 pathway function. STAT1 was sequenced in probands and available relatives. Interferon-induced STAT1 phosphorylation, transcriptional responses, protein-protein interactions, target gene activation, and function were investigated.

Results

We identified 5 patients with disseminated Coccidioides immitis or Histoplasma capsulatum with heterozygous missense mutations in the STAT1 coiled-coil or DNA-binding domains. These are dominant gain-of-function mutations causing enhanced STAT1 phosphorylation, delayed dephosphorylation, enhanced DNA binding and transactivation, and enhanced interaction with protein inhibitor of activated STAT1. The mutations caused enhanced IFN-¦Ã-induced gene expression, but we found impaired responses to IFN-¦Ã restimulation.

Conclusion

Gain-of-function mutations in STAT1 predispose to invasive, severe, disseminated dimorphic yeast infections, likely through aberrant regulation of IFN-¦Ã-mediated inflammation.