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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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Cross talk between Cardif- and MyD88-dependant pathways for efficient clearance of CHIKV. Cardif−/−, MyD88−/−, TLR3−/−, and the corresponding WT controls were infected with 106 PFU. (A) Viral titer was measured at 24 and 48 h after infection. As a control we show infection of an IFNAR−/− animal. (B) Tissues were collected 72 h after infection and viral titers were determined using TCID50. The limits of detection are indicated by dashed lines. Individual mice are represented and geometric means are indicated by bars. It is of note that IFNAR mice are dead at that time point. Mann-Whitney U test was used and, where significant, p-values are reported. Data shown is combined from two independent experiments.
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fig7: Cross talk between Cardif- and MyD88-dependant pathways for efficient clearance of CHIKV. Cardif−/−, MyD88−/−, TLR3−/−, and the corresponding WT controls were infected with 106 PFU. (A) Viral titer was measured at 24 and 48 h after infection. As a control we show infection of an IFNAR−/− animal. (B) Tissues were collected 72 h after infection and viral titers were determined using TCID50. The limits of detection are indicated by dashed lines. Individual mice are represented and geometric means are indicated by bars. It is of note that IFNAR mice are dead at that time point. Mann-Whitney U test was used and, where significant, p-values are reported. Data shown is combined from two independent experiments.

Mentions: To gain better insight into the in vivo response to CHIKV, we infected Cardif−/− (C57BL/6 background) animals and again assessed survival and viral dissemination. Supporting the findings in the RIG-I−/− and Mda5−/−, none of the Cardif−/− mice infected with 106 PFU of CHIKV died from the infection (n = 15). There was, however, a reproducible phenotype. Viral titers in the Cardif−/− were increased as compared with WT mice at 48 h after infection in the serum (Fig. 7 A), and low but detectable levels of virus were found in the skin, joints, liver, muscle, spleen, and serum at 72 h after infection (Fig. 7 B).


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)

Cross talk between Cardif- and MyD88-dependant pathways for efficient clearance of CHIKV. Cardif−/−, MyD88−/−, TLR3−/−, and the corresponding WT controls were infected with 106 PFU. (A) Viral titer was measured at 24 and 48 h after infection. As a control we show infection of an IFNAR−/− animal. (B) Tissues were collected 72 h after infection and viral titers were determined using TCID50. The limits of detection are indicated by dashed lines. Individual mice are represented and geometric means are indicated by bars. It is of note that IFNAR mice are dead at that time point. Mann-Whitney U test was used and, where significant, p-values are reported. 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

fig7: Cross talk between Cardif- and MyD88-dependant pathways for efficient clearance of CHIKV. Cardif−/−, MyD88−/−, TLR3−/−, and the corresponding WT controls were infected with 106 PFU. (A) Viral titer was measured at 24 and 48 h after infection. As a control we show infection of an IFNAR−/− animal. (B) Tissues were collected 72 h after infection and viral titers were determined using TCID50. The limits of detection are indicated by dashed lines. Individual mice are represented and geometric means are indicated by bars. It is of note that IFNAR mice are dead at that time point. Mann-Whitney U test was used and, where significant, p-values are reported. Data shown is combined from two independent experiments.
Mentions: To gain better insight into the in vivo response to CHIKV, we infected Cardif−/− (C57BL/6 background) animals and again assessed survival and viral dissemination. Supporting the findings in the RIG-I−/− and Mda5−/−, none of the Cardif−/− mice infected with 106 PFU of CHIKV died from the infection (n = 15). There was, however, a reproducible phenotype. Viral titers in the Cardif−/− were increased as compared with WT mice at 48 h after infection in the serum (Fig. 7 A), and low but detectable levels of virus were found in the skin, joints, liver, muscle, spleen, and serum at 72 h after infection (Fig. 7 B).

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