The proteome of Toll-like receptor 3–stimulated human immortalized fibroblasts: Implications for susceptibility to herpes simplex virus encephalitis - 30/03/13
, Claire Mulvey, PhD e, Mark Crawford, BSc e, Matthew W.B. Trotter, PhD f, Lazaro Lorenzo, BSc a, b, c, Vanessa Sancho-Shimizu, PhD a, b, c, Laurent Abel, MD, PhD a, b, c, Shen-Ying Zhang, MD, PhD a, b, c, Jean-Laurent Casanova, MD, PhD a, b, c, g, h, Jasminka Godovac-Zimmermann, PhD e
Corresponding author: Rebeca Perez de Diego, PhD, Immunology Unit, IdiPAZ Institute for Health Research, La Paz University Hospital, 261 P° Castellana, Madrid 28046, Spain.Abstract |
Background |
Inborn errors in Toll-like receptor 3 (TLR3)-IFN type I and III pathways have been implicated in susceptibility to herpes simplex virus encephalitis (HSE) in children, but most patients studied do not carry mutations in any of the genes presently associated with HSE susceptibility. Moreover, many patients do not display any TLR3-IFN-related fibroblastic phenotype.
Objective |
To study other signaling pathways downstream of TLR3 and/or other independent pathways that may contribute to HSE susceptibility.
Methods |
We used the stable isotope labeling of amino acids in cell culture proteomics methodology to measure changes in the human immortalized fibroblast proteome after TLR3 activation.
Results |
Cells from healthy controls were compared with cells from a patient with a known genetic etiology of HSE (UNC-93B−/−) and also to cells from an HSE patient with an unknown gene defect. Consistent with known variation in susceptibility of individuals to viral infections, substantial variation in the response level of different healthy controls was observed, but common functional networks could be identified, including upregulation of superoxide dismutase 2. The 2 patients with HSE studied show clear differences in functional response networks when compared with healthy controls and also when compared with each other.
Conclusions |
The present study delineates a number of novel proteins, TLR3-related pathways, and cellular phenotypes that may help elucidate the genetic basis of childhood HSE. Furthermore, our results reveal superoxide dismutase 2 as a potential therapeutic target for amelioration of the neurologic sequelae caused by HSE.
Le texte complet de cet article est disponible en PDF.Key words : Herpes simplex virus encephalitis (HSE), SILAC, proteomics, mass spectrometry, fibroblast, herpes simplex virus 1 (HSV-1), TLR3, IFN
Abbreviations used : CNS, H, HSE, HSV-1, 1ICAM-1, L, MS, poly(I:C), PPIF, SILAC, SOD2, TLR3
Plan
| This study was supported by the AXA Research Fund, Groupement d’Intérêt Scientifique Maladies Rares, Action Concertée Incitative de Microbiologie, the March of Dimes, Agence Nationale pour la Recherche, the Eppley Foundation, the National Institute of Allergy and Infectious Diseases (grant no. R01AI088364), the Thrasher Research Fund, the Jeffrey Modell Foundation, Talecris Biotherapeutics, the St Giles Foundation, the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH) (grant no. 8UL1TR000043), and the Rockefeller University. |
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| Disclosure of potential conflict of interest: R. P. de Diego is supported by a European Union FP6 grant. J.-L. Casanova was an international scholar of the Howard Hughes Medical Institute until 2008. J. Godovac-Zimmermann was supported by a Wellcome Trust Grant. Since initial involvement in the work, M. W. B. Trotter has become an employee of Celgene Research SLU, part of Celgene Corporation, and declares no conflicts of interest. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 131 - N° 4
P. 1157-1166 - avril 2013 Retour au numéro
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