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, 88 (23), 13593-601

Sendai Virus Pathogenesis in Mice Is Prevented by Ifit2 and Exacerbated by Interferon

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Sendai Virus Pathogenesis in Mice Is Prevented by Ifit2 and Exacerbated by Interferon

Jaime L Wetzel et al. J Virol.

Abstract

The type I/III interferon (IFN) system has major roles in regulating viral pathogenesis, usually ameliorating pathogenesis by impairing virus replication through the antiviral actions of one or more IFN-induced proteins. Ifit2 is one such protein which can be induced by IFN or virus infection, and it is responsible for protecting mice from neuropathogenesis caused by vesicular stomatitis virus. Here, we show that Ifit2 also protects mice from pathogenesis caused by the respirovirus Sendai virus (SeV). Mice lacking Ifit2 (Ifit2(-/-)) suffered severe weight loss and succumbed to intranasal infection with SeV strain 52 at a dose that killed only a few wild-type mice. Viral RNA was detectable only in lungs, and SeV titers were higher in Ifit2(-/-) mice than in wild-type mice. Similar infiltration of immune cells was found in the lungs of both mouse lines, corresponding to similar levels of many induced cytokines and chemokines. In contrast, IFN-β and IFN-λ3 expression were considerably higher in the lungs of Ifit2(-/-) mice. Surprisingly, type I IFN receptor knockout (IFNAR(-/-)) mice were less susceptible to SeV than Ifit2(-/-) mice, although their pulmonary virus titers were similarly high. To test the intriguing possibility that type I IFN action enhances pathogenesis in the context of elevated SeV replication in lungs, we generated Ifit2/IFNAR(-/-) double knockout mice. These mice were less susceptible to SeV than Ifit2(-/-) mice, although viral titers in their lungs were even higher. Our results indicate that high SeV replication in the lungs of infected Ifit2(-/-) mice cooperates with elevated IFN-β induction to cause disease.

Importance: The IFN system is an innate defense against virus infections. It is triggered quickly in infected cells, which then secrete IFN. Via their cell surface receptors on surrounding cells, they induce transcription of numerous IFN-stimulated genes (ISG), which in turn protect these cells by inhibiting virus life cycles. Hence, IFNs are commonly considered beneficial during virus infections. Here, we report two key findings. First, lack of a single ISG in mice, Ifit2, resulted in high mortality after SeV infection of the respiratory tract, following higher virus loads and higher IFN production in Ifit2(-/-) lungs. Second, mortality of Ifit2(-/-) mice was reduced when mice also lacked the type I IFN receptor, while SeV loads in lungs still were high. This indicates that type I IFN exacerbates pathogenesis in the SeV model, and that limitation of both viral replication and IFN production is needed for effective prevention of disease.

Figures

FIG 1
FIG 1
Ifit2 protects against morbidity and mortality after SeV infection. Survival of wt and Ifit2−/− mice after SeV infection with low dose (0.34 × 105 PFU) (A), medium dose (1.2 × 105 PFU) (B), or high dose (4.9 × 105 PFU) (C). (D) Weight loss of wt and Ifit2−/− mice infected with the medium SeV dose; the number of surviving mice is indicated on the right. (E) Survival of IFNAR−/− and wt mice infected with the medium SeV dose. Asterisks indicate statistical significance.
FIG 2
FIG 2
Ifit2 and type I IFN limit SeV replication in lungs. (A) SeV RNA levels in different organs from wt and Ifit2−/− mice (n = 3) at 5 dpi, measured by real-time RT-PCR. (B) SeV RNA in lungs of wt, Ifit2−/−, and IFNAR−/− mice (n = 4 to 8) at different times after infection. (C) Infectious SeV titers in lungs of wt, Ifit2−/−, and IFNAR−/− mice (n = 3 to 5) at different times after infection. Asterisks indicate statistical significance. ND, not detected.
FIG 3
FIG 3
Increased type I and III interferon induction in Ifit2−/− and IFNAR−/− lungs after SeV infection. Ifit1 (A), Ifit2 (B), IFN-β (C), and IFN-λ3 (D) mRNA expression in lungs of wt, Ifit2−/−, and IFNAR−/− mice (n = 3 to 7) after SeV infection, measured by real-time RT-PCR. Asterisks indicate statistical significance; n.s., not significant; ND, not detected.
FIG 4
FIG 4
Elevated production of IFN-β, but not of other cytokines, in Ifit2−/− lungs after SeV infection. (A) IFN-β protein levels in wt, Ifit2−/−, and IFNAR−/− lung homogenates after SeV infection, measured by ELISA (n = 3 to 5). (B and C) Cytokine and chemokine protein levels in wt, Ifit2−/−, and IFNAR−/− lung homogenates at 5 days after SeV infection, measured by multiplex ELISA (n = 3). Asterisks indicate statistical significance.
FIG 5
FIG 5
Similar infiltration by immune cells in wt and Ifit2−/− lungs after SeV infection. (A) Cell numbers in BAL fluid of wt and Ifit2−/− mice at different times after SeV infection (n = 3). (B) Accumulation of immune cell marker mRNAs in wt and Ifit2−/− whole-lung tissue (n = 4) after SeV infection, measured by real-time RT-PCR. No statistically significant differences between wt and Ifit2−/− were found.
FIG 6
FIG 6
High SeV dose increases pathogenesis and IFN-β induction but not subsequent virus replication in wt mice. Survival of wt (A) and IFNAR−/− (B) mice after infection with medium or high SeV dose. (C) Infectious SeV titers in lungs of wt, Ifit2−/−, and IFNAR−/− mice (n = 3 to 5) at 5 days after infection with medium or high SeV dose. (D) IFN-β mRNA expression in lungs of wt, Ifit2−/−, and IFNAR−/− mice (n = 4 to 6) at 2 days after SeV infection (medium or high dose), measured by real-time RT-PCR. Data shown panels A and B are derived from data depicted in Fig. 1B, C, and E. Data for medium dose infection in panels C and D are partially derived from data shown in Fig. 2C and 3C, respectively. Asterisks indicate statistical significance; n.s., not significant.
FIG 7
FIG 7
Type I IFN exacerbates SeV pathogenesis in the absence of Ifit2. (A) Survival of wt, Ifit2−/−, and DKO (Ifit2−/−, IFNAR−/−) mice after infection with a low, medium, or high SeV dose. IFN-β (B) and IFN-λ3 (C) mRNA expression in lungs of wt and DKO mice (n = 5) 2 days after SeV infection (medium or high dose dose), measured by real-time RT-PCR. (D) Infectious SeV titers in lungs of wt, Ifit2−/−, IFNAR−/−, and DKO mice (n = 3 to 5) at 5 days after infection with medium or high SeV dose. Experiments shown in panel A used the same wt and Ifit2−/− mice as those used for Fig. 1A, B, C. Panel D is partially derived from Fig. 6C. Asterisks indicate statistical significance; n.s., not significant.

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