Signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations and disseminated coccidioidomycosis and histoplasmosis - 30/05/13

Doi : 10.1016/j.jaci.2013.01.052

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, PhD ⁱ, Brendan De Marco, MD ⁱ, Michael Alvares, MD ^j, Jason W. Gillman, MD ⁱ, Vivek Ramarathnam, MD ⁱ, 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, MD ⁱ, Susan E. Hoover, MD, PhD ⁿ, Sergio D. Rosenzweig, MD, PhD ^h,^o, John N. Galgiani, MD ⁿ, Steven M. Holland, MD ^a,^⁎
^a Immunopathogenesis Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Md
^f Allergic Inflammation Unit, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Md
^h Infectious Diseases Susceptibility Unit, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Md
^o Primary Immunodeficiency Clinic, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Md
^b Leprosy Laboratory, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, Brazil
^c Department of Internal Medicine and Department of Medical Microbiology and Infectious Diseases, Erasmus Medical Center, Rotterdam, The Netherlands
^d Clinical Research Directorate/CMRP, SAIC-Frederick, NCI-Frederick, Frederick, Md
^g Clinical Services Program, SAIC-Frederick, NCI-Frederick, Frederick, Md
^e Division of Infectious Diseases, McGill University Health Centre, Montreal, Quebec, Canada
ⁱ Division of Infectious Diseases, University of Texas Southwestern Medical Center, Dallas, Tex
^j Division of Allergy and Immunology, University of Texas Southwestern Medical Center, Dallas, Tex
^k Immunology Unit, Pediatric Hospital R. Gutierrez, Buenos Aires, Argentina
^l Comer Children's Hospital, University of Chicago, Chicago, Ill
^m Clinical Trials Branch, National Eye Institute, NIH, Bethesda, Md
ⁿ Valley Fever Center for Excellence, University of Arizona College of Medicine, Tucson, Ariz

^∗Corresponding author: Steven M. Holland, MD, CRC B3-4141 MSC 1684, Bethesda, MD 20892-1684.

Abstract

Background

Impaired signaling in the IFN-γ/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-γ/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-γ–induced gene expression, but we found impaired responses to IFN-γ restimulation.

Conclusion

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

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Key words : Signal transducer and activator of transcription 1, IFN-γ, progressive multifocal leukoencephalopathy, Histoplasma capsulatum, Coccidioides immitis, thrush

Abbreviations used : CMC, CSF, CT, DMA, GAS, GFP, ISRE, L-AmB, MRI, NIH, PIAS, PML, pSTAT1, SAMe, siRNA, STAT1, WB, WT

Plan

Methods

Patients and blood samples

Evaluation of STAT1 activation

Downregulation of PIAS1

Delayed STAT1 dephosphorylation, enhanced DNA binding, and transactivation

PIAS1-STAT1 interaction

Gene expression

Cytokine production and evaluation of T_H17 response

Discussion

Supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, and funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.

Disclosure of potential conflict of interest: D. C. Vinh has received research support from the Canadian Institutes of Health Research Post-doctoral Fellowship, CSL Behring Canada, and Astellas Canada; has consultant arrangements with CSL Behring Canada and Pfizer Canada; and has received payment for lectures from CSL Behring Canada and Sunovion/Sepracor. D. B. Kuhns and D. A. Long Priel have received grants from the National Cancer Institute/National Institutes of Health. V. Ramarathnam is employed by Private Practice ID. S. D. Rosenzweig receives royalties from UpToDate. The rest of the authors declare that they have no relevant conflicts of interest.

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Vol 131 - N° 6

P. 1624 - juin 2013 Retour au numéro

Article précédent

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Signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations and disseminated coccidioidomycosis and histoplasmosis - 30/05/13

Abstract

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Conclusion

Plan

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