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Type I IFN controls chikungunya virus via its action on nonhematopoietic cells.

Schilte C, Couderc T, Chretien F, Sourisseau M, Gangneux N, Guivel-Benhassine F, Kraxner A, Tschopp J, Higgs S, Michault A, Arenzana-Seisdedos F, Colonna M, Peduto L, Schwartz O, Lecuit M, Albert ML - J. Exp. Med. (2010)

Bottom Line: Based on human studies and mouse experimentation, we show that CHIKV does not directly stimulate type I IFN production in immune cells.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Immunology, Unité Immunobiologie des Cellules Dendritiques, Institut Pasteur, 75724 Paris, Cedex 15, France.

ABSTRACT
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.

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Cell-intrinsic control of CHIKV in fibroblasts is mediated by intracellular sensors. (A) Cardif−/− and the corresponding WT control MEFs were infected with increasing MOI of CHIKV. At 48 h, cells were analyzed by FACS for expression of CHIKV antigens. (B) Culture supernatants were harvested at 48 h and analyzed for IFN-β protein. As a positive control, MEFs were exposed to FluΔNS1. (C) IFN-β mRNA induction was measured by RT-PCR at 24 h after infection. The mean of three independent experiments is shown. Error bars show SD.
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fig5: Cell-intrinsic control of CHIKV in fibroblasts is mediated by intracellular sensors. (A) Cardif−/− and the corresponding WT control MEFs were infected with increasing MOI of CHIKV. At 48 h, cells were analyzed by FACS for expression of CHIKV antigens. (B) Culture supernatants were harvested at 48 h and analyzed for IFN-β protein. As a positive control, MEFs were exposed to FluΔNS1. (C) IFN-β mRNA induction was measured by RT-PCR at 24 h after infection. The mean of three independent experiments is shown. Error bars show SD.

Mentions: Cardif−/− MEFs were exposed to increasing MOI of virus and CHIKV antigen expression was monitored. Cardif−/− MEFs were more sensitive to infection than their WT counterparts, especially at a lower MOI (Fig. 5 A). We next evaluated IFN production and, strikingly, the Cardif−/− MEFs failed to produce IFN-β (Fig. 5 B) This was confirmed at the RNA level with the Cardif−/− expressing 500-fold less IFN-β mRNA as compared with the WT MEFs (Fig. 5 C). Based on these data, we suggest that infected fibroblasts respond to CHIKV infection via a Cardif-dependant sensor, producing type I IFNs and limiting infection.


Type I IFN controls chikungunya virus via its action on nonhematopoietic cells.

Schilte C, Couderc T, Chretien F, Sourisseau M, Gangneux N, Guivel-Benhassine F, Kraxner A, Tschopp J, Higgs S, Michault A, Arenzana-Seisdedos F, Colonna M, Peduto L, Schwartz O, Lecuit M, Albert ML - J. Exp. Med. (2010)

Cell-intrinsic control of CHIKV in fibroblasts is mediated by intracellular sensors. (A) Cardif−/− and the corresponding WT control MEFs were infected with increasing MOI of CHIKV. At 48 h, cells were analyzed by FACS for expression of CHIKV antigens. (B) Culture supernatants were harvested at 48 h and analyzed for IFN-β protein. As a positive control, MEFs were exposed to FluΔNS1. (C) IFN-β mRNA induction was measured by RT-PCR at 24 h after infection. The mean of three independent experiments is shown. Error bars show SD.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2822618&req=5

fig5: Cell-intrinsic control of CHIKV in fibroblasts is mediated by intracellular sensors. (A) Cardif−/− and the corresponding WT control MEFs were infected with increasing MOI of CHIKV. At 48 h, cells were analyzed by FACS for expression of CHIKV antigens. (B) Culture supernatants were harvested at 48 h and analyzed for IFN-β protein. As a positive control, MEFs were exposed to FluΔNS1. (C) IFN-β mRNA induction was measured by RT-PCR at 24 h after infection. The mean of three independent experiments is shown. Error bars show SD.
Mentions: Cardif−/− MEFs were exposed to increasing MOI of virus and CHIKV antigen expression was monitored. Cardif−/− MEFs were more sensitive to infection than their WT counterparts, especially at a lower MOI (Fig. 5 A). We next evaluated IFN production and, strikingly, the Cardif−/− MEFs failed to produce IFN-β (Fig. 5 B) This was confirmed at the RNA level with the Cardif−/− expressing 500-fold less IFN-β mRNA as compared with the WT MEFs (Fig. 5 C). Based on these data, we suggest that infected fibroblasts respond to CHIKV infection via a Cardif-dependant sensor, producing type I IFNs and limiting infection.

Bottom Line: Based on human studies and mouse experimentation, we show that CHIKV does not directly stimulate type I IFN production in immune cells.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Immunology, Unité Immunobiologie des Cellules Dendritiques, Institut Pasteur, 75724 Paris, Cedex 15, France.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus