Type I IFN controls chikungunya virus via its action on nonhematopoietic cells.
Chikungunya virus (CHIKV) is the causative agent of an outbreak that began in La Réunion in 2005 and remains a major public health concern in India, Southeast Asia, and southern Europe. CHIKV is transmitted to humans by mosquitoes and the associated disease is characterized by fever, myalgia, arthralgia, and rash. As viral load in infected patients declines before the appearance of neutralizing antibodies, we studied the role of type I interferon (IFN) in CHIKV pathogenesis. Based on human studies and mouse experimentation, we show that CHIKV does not directly stimulate type I IFN production in immune cells. Instead, infected nonhematopoietic cells sense viral RNA in a Cardif-dependent manner and participate in the control of infection through their production of type I IFNs. Although the Cardif signaling pathway contributes to the immune response, we also find evidence for a MyD88-dependent sensor that is critical for preventing viral dissemination. Moreover, we demonstrate that IFN-alpha/beta receptor (IFNAR) expression is required in the periphery but not on immune cells, as IFNAR(-/-)-->WT bone marrow chimeras are capable of clearing the infection, whereas WT-->IFNAR(-/-) chimeras succumb. This study defines an essential role for type I IFN, produced via cooperation between multiple host sensors and acting directly on nonhematopoietic cells, in the control of CHIKV.
Schilte
Clémentine
C
Department of Immunology, Unité Immunobiologie des Cellules Dendritiques, Institut Pasteur, 75724 Paris, Cedex 15, France.
Couderc
Thérèse
T
Chretien
Fabrice
F
Sourisseau
Marion
M
Gangneux
Nicolas
N
Guivel-Benhassine
Florence
F
Kraxner
Anton
A
Tschopp
Jürg
J
Higgs
Stephen
S
Michault
Alain
A
Arenzana-Seisdedos
Fernando
F
Colonna
Marco
M
Peduto
Lucie
L
Schwartz
Olivier
O
Lecuit
Marc
M
Albert
Matthew L
ML
D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology / Q000378:metabolism; D018354:Alphavirus Infections / Q000097:blood / Q000276:immunology* / Q000821:virology; D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood / Q000276:immunology; D000914:Antibodies, Viral / Q000097:blood / Q000276:immunology; D001773:Blood Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology; D002646:Chikungunya virus; D006801:Humans; D007370:Interferon Type I / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D012367:RNA, Viral; D053633:Receptor, Interferon alpha-beta / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D019562:Viral Load
D048868:Adaptor Proteins, Signal Transducing; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D007370:Interferon Type I; D012367:RNA, Viral; D053633:Receptor, Interferon alpha-beta