%0 Journal Article %T ISG15 Is Critical in the Control of Chikungunya Virus Infection Independent of UbE1L Mediated Conjugation %+ Washington University School of Medicine %+ Immunobiologie des Cellules Dendritiques %+ Centre Hospitalier Universitaire de La Réunion (CHU La Réunion) %+ Pathogénie Virale Moléculaire %+ The University of Texas Medical Branch (UTMB) %+ Kansas State University %+ Epidémiologie des Maladies Emergentes - Emerging Diseases Epidemiology %A Werneke, Scott W. %A Schilte, Clementine %A Rohatgi, Anjali %A Monte, Kristen J. %A Michault, Alain %A Arenzana-Seisdedos, Fernando %A Vanlandingham, Dana L. %A Higgs, Stephen %A Fontanet, Arnaud %A Albert, Matthew L. %A Lenschow, Deborah J. %Z D.J.L. was supported by a developmental award from NIH grant U54 AI05716007, a Pew Scholar Award, and an award from the Children's Discovery Institute. S.W. was supported by T32 AI00717231. M.L.A. acknowledges the L'Agence nationale de la recherché (ANR) for support of the research. Washington University Hybridoma Core facility and transgenic core facility was supported by NIH P30 AR048335. D.V. and S.H were in part supported by NIH AI R21 AI073389. %< avec comité de lecture %@ 1553-7366 %J PLoS Pathogens %I Public Library of Science %V 7 %N 10 %P e1002322 %8 2011-10-20 %D 2011 %R 10.1371/journal.ppat.1002322 %M 22028657 %K Chikungunya infection %K Cytokines %K Interferons %K Viral load %K Neonates %K Conjugated proteins %K Mouse models %K Immune response %Z Life Sciences [q-bio]/ImmunologyJournal articles %X Chikungunya virus (CHIKV) is a re-emerging alphavirus that has caused significant disease in the Indian Ocean region since 2005. During this outbreak, in addition to fever, rash and arthritis, severe cases of CHIKV infection have been observed in infants. Challenging the notion that the innate immune response in infants is immature or defective, we demonstrate that both human infants and neonatal mice generate a robust type I interferon (IFN) response during CHIKV infection that contributes to, but is insufficient for, the complete control of infection. To characterize the mechanism by which type I IFNs control CHIKV infection, we evaluated the role of ISG15 and defined it as a central player in the host response, as neonatal mice lacking ISG15 were profoundly susceptible to CHIKV infection. Surprisingly, UbE1L 2/2 mice, which lack the ISG15 E1 enzyme and therefore are unable to form ISG15 conjugates, displayed no increase in lethality following CHIKV infection, thus pointing to a non-classical role for ISG15. No differences in viral loads were observed between wild-type (WT) and ISG15 2/2 mice, however, a dramatic increase in proinflammatory cytokines and chemokines was observed in ISG15 2/2 mice, suggesting that the innate immune response to CHIKV contributes to their lethality. This study provides new insight into the control of CHIKV infection, and establishes a new model for how ISG15 functions as an immunomodulatory molecule in the blunting of potentially pathologic levels of innate effector molecules during the host response to viral infection. %G English %Z We thank the Centre d'Immunologie Humaine and the CHIKV Task Force from the Institut Pasteur for support of this work and access to critical reagents. We also acknowledge Olivier Schwartz for helpful suggestions and for the careful review of the manuscript. We thank Kristen Monte and Charlotte Auriau for their outstanding expertise in animal care; and Stéphanie Thomas for support in sample transportation and filing of regulatory procedures. %2 https://pasteur.hal.science/pasteur-01402061/document %2 https://pasteur.hal.science/pasteur-01402061/file/journal.ppat.1002322.PDF %L pasteur-01402061 %U https://pasteur.hal.science/pasteur-01402061 %~ INSERM %~ PASTEUR %~ CNAM %~ ATP-IMMUN %~ TEST3-HALCNRS %~ HESAM-CNAM %~ HESAM