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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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CHIKV-infected IFNAR−/− mice produce high levels of type I IFNs. (A) C57BL/6 IFNAR−/− mice were infected ID with 102 PFU or 106 PFU CHIKV. Survival was assessed twice a day and Kaplan-Meier survival curves were drawn (n = 5). (B) STAT1−/−, STAT4−/−, and STAT6−/− (n = 5) mice, along with corresponding WT mice of a similar strain background, were infected ID with 106 PFU CHIKV. Survival was assessed twice a day and Kaplan-Meier survival curves were drawn. (C and D) WT and IFNAR−/− mice were infected with 106 PFU CHIKV and serum concentrations of IFN-β and IFN-α were monitored at day 2 after infection. Each dot represents an individual mouse, horizontal bars represent the mean. Data shown is combined from two independent experiments.
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fig2: CHIKV-infected IFNAR−/− mice produce high levels of type I IFNs. (A) C57BL/6 IFNAR−/− mice were infected ID with 102 PFU or 106 PFU CHIKV. Survival was assessed twice a day and Kaplan-Meier survival curves were drawn (n = 5). (B) STAT1−/−, STAT4−/−, and STAT6−/− (n = 5) mice, along with corresponding WT mice of a similar strain background, were infected ID with 106 PFU CHIKV. Survival was assessed twice a day and Kaplan-Meier survival curves were drawn. (C and D) WT and IFNAR−/− mice were infected with 106 PFU CHIKV and serum concentrations of IFN-β and IFN-α were monitored at day 2 after infection. Each dot represents an individual mouse, horizontal bars represent the mean. Data shown is combined from two independent experiments.

Mentions: To better define the role of IFN in the control of CHIKV and to identify the viral sensor responsible for its production, we developed a mouse model for CHIKV infection. Using IFNAR−/− mice on the C57BL/6 strain, it was possible to demonstrate a critical role for IFNAR signaling in the control of CHIKV. Remarkably, 102 PFU injected intradermally (ID) was sufficient to kill the IFNAR−/− mice between days 2.5 and 4 after infection (Fig. 2 A). Injection of 106 PFU resulted in even faster death with all animals succumbing to infection between days 2 and 3. Similar to what was observed in highly viremic humans (Fig. 1 A; Laurent et al., 2007), the viral load in IFNAR−/− mice infected with 106 PFU at 2 d after infection was >108 tissue culture infectious dose 50 (TCID50)/ml (not depicted). In contrast, WT animals cleared the infection with undetectable serum viral titers at all time points tested. These data are similar to those reported for IFNAR−/− mice on the 129 strain (Couderc et al., 2008).


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)

CHIKV-infected IFNAR−/− mice produce high levels of type I IFNs. (A) C57BL/6 IFNAR−/− mice were infected ID with 102 PFU or 106 PFU CHIKV. Survival was assessed twice a day and Kaplan-Meier survival curves were drawn (n = 5). (B) STAT1−/−, STAT4−/−, and STAT6−/− (n = 5) mice, along with corresponding WT mice of a similar strain background, were infected ID with 106 PFU CHIKV. Survival was assessed twice a day and Kaplan-Meier survival curves were drawn. (C and D) WT and IFNAR−/− mice were infected with 106 PFU CHIKV and serum concentrations of IFN-β and IFN-α were monitored at day 2 after infection. Each dot represents an individual mouse, horizontal bars represent the mean. Data shown is combined from two independent experiments.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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

fig2: CHIKV-infected IFNAR−/− mice produce high levels of type I IFNs. (A) C57BL/6 IFNAR−/− mice were infected ID with 102 PFU or 106 PFU CHIKV. Survival was assessed twice a day and Kaplan-Meier survival curves were drawn (n = 5). (B) STAT1−/−, STAT4−/−, and STAT6−/− (n = 5) mice, along with corresponding WT mice of a similar strain background, were infected ID with 106 PFU CHIKV. Survival was assessed twice a day and Kaplan-Meier survival curves were drawn. (C and D) WT and IFNAR−/− mice were infected with 106 PFU CHIKV and serum concentrations of IFN-β and IFN-α were monitored at day 2 after infection. Each dot represents an individual mouse, horizontal bars represent the mean. Data shown is combined from two independent experiments.
Mentions: To better define the role of IFN in the control of CHIKV and to identify the viral sensor responsible for its production, we developed a mouse model for CHIKV infection. Using IFNAR−/− mice on the C57BL/6 strain, it was possible to demonstrate a critical role for IFNAR signaling in the control of CHIKV. Remarkably, 102 PFU injected intradermally (ID) was sufficient to kill the IFNAR−/− mice between days 2.5 and 4 after infection (Fig. 2 A). Injection of 106 PFU resulted in even faster death with all animals succumbing to infection between days 2 and 3. Similar to what was observed in highly viremic humans (Fig. 1 A; Laurent et al., 2007), the viral load in IFNAR−/− mice infected with 106 PFU at 2 d after infection was >108 tissue culture infectious dose 50 (TCID50)/ml (not depicted). In contrast, WT animals cleared the infection with undetectable serum viral titers at all time points tested. These data are similar to those reported for IFNAR−/− mice on the 129 strain (Couderc et al., 2008).

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