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. 2010 Nov;84(21):11515-22.
doi: 10.1128/JVI.01703-09. Epub 2010 Aug 25.

Lambda interferon is the predominant interferon induced by influenza A virus infection in vivo

Nancy A Jewell  1 , Troy Cline, Sara E Mertz, Sergey V Smirnov, Emilio Flaño, Christian Schindler, Jessica L Grieves, Russell K Durbin, Sergei V Kotenko, Joan E Durbin
Affiliations

Lambda interferon is the predominant interferon induced by influenza A virus infection in vivo

Nancy A Jewell et al. J Virol. 2010 Nov.

Erratum in

  • J Virol. 2011 Jan;85(1):650

Abstract

The type I alpha/beta interferons (IFN-α/β) are known to play an important role in host defense against influenza A virus infection, but we have now discovered that the recently identified type III IFNs (IFN-λ) constitute the major response to intranasal infection with this virus. Type III IFNs were present at much higher levels than type I IFNs in the lungs of infected mice, and the enhanced susceptibility of STAT2-/- animals demonstrated that only signaling through the IFN-α/β or IFN-λ pathways was sufficient to mediate protection. This finding offers a possible explanation for the similar levels of antiviral protection found in wild-type (WT) mice and in animals lacking a functional type I IFN receptor (IFNAR-/-) but also argues that our current understanding of type III IFN induction is incomplete. While murine IFN-λ production is thought to depend on signaling through the type I IFN receptor, we demonstrate that intranasal influenza A virus infection leads to the robust type III IFN induction in the lungs of both WT and IFNAR-/- mice. This is consistent with previous studies showing that IFNAR-mediated protection is redundant for mucosal influenza virus infection and with data showing that the type III IFN receptor is expressed primarily by epithelial cells. However, the overlapping effects of these two cytokine families are limited by their differential receptor expression, with a requirement for IFN-α/β signaling in combating systemic disease.

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Figures

FIG. 1.
FIG. 1.
Infection with influenza virus induced significantly more IFN-λ than IFN-α. Cohorts of BALB/c wild-type (A) or IFNAR−/− (B) mice (n = 4) were infected i.n. with 104 PFU of influenza A/WSN/33, and BAL samples were harvested 24, 48, 72, or 96 h postinfection. Concentrations of IFN-α (black bars) and IFN-λ (white bars) were determined by ELISA. Data represent the means and standard errors of the means. (C) Results of an assay of IFN-α/β and IFN-λ2 antiviral activity on the mouse lung epithelial cell line MLE-15.
FIG. 2.
FIG. 2.
Dose dependence of IFN-λ induced by WSN virus infection. (A) Wild-type BALB/c mice (n = 4) were infected i.n. with 102, 104, or 106 PFU of influenza A/WSN/33, and BAL samples from infected animals were harvested 24 (black bars), 48 (white bars), 72 (gray bars), or 96 (hatched bars) hours postinfection. IFN-λ protein levels were determined by ELISA. Data represent the means and standard errors of the means. (B) Chinese hamster cells expressing a chimeric human IFN-λ receptor complex were left untreated (lane 1), treated with recombinant murine IFN-λ2 at 10 ng/150 μl, 1 ng/150 μl, 0.1 ng/150 μl, and 0.01 ng/150 μl (lanes 2 to 5, respectively), or incubated with BAL samples from BALB/c mice infected i.n. with 106 PFU of WSN. Either 20 μl (a) or 2 μl (b) of BAL fluid was added to the samples, for a total volume of 150 μl. Shown are assay results from individual animals at 48 h (lanes 6 and 7), 72 h (lanes 8 and 9), and 96 h (lanes 10 and 11) postinfection. After a 15-min incubation with the sample, the indicator cells were lysed, and nuclear extracts were assayed by EMSA for STAT1 activation. Recombinant murine IFN-λ2 of a known concentration was used as a standard (lanes 2, 3, 4, and 5). The arrow denotes STAT1:STAT1 homodimers. No signal was present in BAL fluid harvested from uninfected mice (data not shown).
FIG. 3.
FIG. 3.
Both IFN-α and IFN-λ are secreted by pDCs following influenza A infection. BMDCs cultured with FLT-3 ligand were mock infected or infected with WSN (live or UV inactivated) at an MOI of 1 or treated with CpG (2 μg/ml). At 24 h postinfection, the DC supernatants were assayed by ELISA for the presence of IFN-λ (A) or IFN-α (B) protein. Data represent the means and standard deviations of results from three replicate samples.
FIG. 4.
FIG. 4.
Control of influenza A virus infection is STAT1 and STAT2 dependent but IFN-α/β independent. (A) Cohorts of 6- to 8-week-old 129Sv mice of the indicated genotypes were infected i.n. with 100 PFU of influenza virus A/HK-X31. Titers (expressed as fluorescent focus units per gram of lung tissue) were determined by fluorescent focus assay of lung homogenates collected on day 3 after infection. (B) Susceptibility of 129SvEv wild-type, IFNAR−/−, STAT1−/−, and STAT2−/− mice to influenza virus was compared following infection with 100 PFU. Five or six 6- to 8-week-old mice of each strain were used. The percent survival for each group is shown.
FIG. 5.
FIG. 5.
IFN-λ is induced in the airways of wild-type and IFNAR−/− 129SvEv mice by influenza virus A/HK-X31 infection. BAL samples collected from cohorts (n = 5) of HK-X31-infected WT (A) or IFNAR−/− (B) 129Sv mice were assayed by ELISA to determine concentrations of IFN-α and IFN-λ proteins. Data represent the means and standard errors of the means.
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