ISG15 is critical in the control of Chikungunya virus infection independent of UbE1L mediated conjugation.
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⁻/⁻ 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⁻/⁻ mice, however, a dramatic increase in proinflammatory cytokines and chemokines was observed in ISG15⁻/⁻ 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.
Department of Medicine, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
Scott W
SW
Werneke
Clementine
C
Schilte
Anjali
A
Rohatgi
Kristen J
KJ
Monte
Alain
A
Michault
Fernando
F
Arenzana-Seisdedos
Dana L
DL
Vanlandingham
Stephen
S
Higgs
Arnaud
A
Fontanet
Matthew L
ML
Albert
Deborah J
DJ
Lenschow
D018354:Alphavirus Infections / Q000175:diagnosis / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D065632:Chikungunya Fever; D002646:Chikungunya virus / Q000472:pathogenicity / Q000502:physiology*; D016207:Cytokines / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007370:Interferon Type I / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011485:Protein Binding; D011995:Recombination, Genetic; D012189:Retrospective Studies; D044764:Ubiquitin-Activating Enzymes / Q000276:immunology* / Q000378:metabolism; D014452:Ubiquitins / Q000276:immunology* / Q000378:metabolism
D016207:Cytokines; C489550:G1p2 protein, mouse; D007370:Interferon Type I; D014452:Ubiquitins; C074034:ISG15 protein, human; C534879:UBA7 protein, human; D044764:Ubiquitin-Activating Enzymes