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. 2013 Apr 12;340(6129):207-11.
doi: 10.1126/science.1235214.

Persistent LCMV infection is controlled by blockade of type I interferon signaling

John R Teijaro  1 , Cherie Ng, Andrew M Lee, Brian M Sullivan, Kathleen C F Sheehan, Megan Welch, Robert D Schreiber, Juan Carlos de la Torre, Michael B A Oldstone
Affiliations

Persistent LCMV infection is controlled by blockade of type I interferon signaling

John R Teijaro et al. Science. .

Abstract

During persistent viral infections, chronic immune activation, negative immune regulator expression, an elevated interferon signature, and lymphoid tissue destruction correlate with disease progression. We demonstrated that blockade of type I interferon (IFN-I) signaling using an IFN-I receptor neutralizing antibody reduced immune system activation, decreased expression of negative immune regulatory molecules, and restored lymphoid architecture in mice persistently infected with lymphocytic choriomeningitis virus. IFN-I blockade before and after establishment of persistent virus infection resulted in enhanced virus clearance and was CD4 T cell-dependent. Hence, we demonstrate a direct causal link between IFN-I signaling, immune activation, negative immune regulator expression, lymphoid tissue disorganization, and virus persistence. Our results suggest that therapies targeting IFN-I may help control persistent virus infections.

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Figures

Figure 1
Figure 1
IFN-I is elevated early following onset of persistent virus infection. Serum levels of interferon beta (A) and interferon alpha species (B) as measured by ELISA following initiation of persistent Cl13 or acute Arm infections in mice at 18, 24, 48, 120 and 240 hours post-infection in C57BL/6J mice. (C) pDCs are preferentially infected early following Cl13-infection. Percent of GFP positive pDCs infected with ΔGP clone-13 or Armstrong GFP viruses 24 hours post-infection. *, p < 0.05; **, p < 0.01; ***, p < 0.005. Results are representative of 2–3 independent experiments and represent the SEM from 3–5 mice/group.
Figure 2
Figure 2
IFN-I signaling is essential for the expression of the negative immune regulators IL-10 and PD-L1 and lymphoid tissue disorganization following persistent virus infection. Mice were treated with anti-IFNAR1 antibody 1 day prior to infection. (A) Serum levels of IL-10 as measured by ELISA on day 1, 5 and 9 post clone-13 infection in C57BL/6J mice treated with either isotype control or anti-IFNAR1 antibodies. (B) Mean fluorescent intensity (MFI) of PD-L1 expression as determined by flow cytometry on either LCMV viral antigen positive (VL-4+) or viral antigen negative (VL-4−) splenic DCs day 1 post clone-13 infection. (C) Representative histograms of PD-L1 expression as determined by flow cytometry on either infected or uninfected (shaded histograms) CD8α-negative DCs (left) or compiled PD-L1 expression (right) at day 5 post-Cl13 infection. (D) Histogram of PD-L1 expression (left) and mean fluorescent intensity (right) as determined by flow cytometry on splenic CD8α-negative dendritic cells at day 9 post-Cl13 infection. Histopathological and immunofluorescent analysis of spleens day 9 (E) and day 14 (F) post Cl13 infection from naïve mice or mice infected with Cl13 and treated with isotype or anti-IFNAR1 antibodies as done above. Top row: H & E histopathological analysis. Middle row: staining for a stromal cell marker (ER-TR7, a marker for fibroblastic reticular cells) and T-cells (CD3). Bottom row: B cell staining (B220). Images were taken using a 5x objective . Scale bars = 500µm. *, p < 0.05; **, p < 0.01; ***, p < 0.005. Results are representative of 2 independent experiments and represent the SEM from 5 mice/group.
Figure 3
Figure 3
IFN-I signaling blockade controls persistent virus infection. C57BL/6J mice were treated with either isotype control or IFNAR1 antibody 1 day prior to infection with Cl13 (A, B) or 10 days post-Cl13 infection (C–D). (A) Serum viral titers determined by plaque assay at the indicated times post-infection. (B) Viral titers in serum or indicated tissues at day 40 post infection. (C&D) Mice were infected with Cl13 and 10 days post-infection treated with 3 doses of anti-IFNAR1 antibody (500ug, Days 10 & 12 and 250ug day 14). The graph illustrates serum titers of mice 50 days post-infection in the serum (C), lung and liver (D). *, p < 0.05; **, p < 0.01; ***, p < 0.005 #, p=0.07. Results are representative of more than 5 independent experiments and represent the SEM from 5 mice per group.
Figure 4
Figure 4
Control of persistent virus by IFN-I blockade correlates with altered T-cell trafficking and requires CD4 T-cells. C57Bl/6J mice were treated with isotype control or IFNAR1 antibody prior to infection with CL13. (A) At 5 and 14 days post-infection, mice received adoptive transfers of CFSE-labeled naïve T-cells. 2 h after transfer, spleens were harvested to analyze homing and localization of naïve T-cells (green) to T-cell zones (CD3, red; fibroblastic reticular cells (ER-TR7), blue). Images were taken using a 20x objective. Scale bars = 100µm. (B) Quantitation of naïve T-cell localization. The number of transferred CFSE-labeled naïve T-cells was counted in ten random white pulp regions per spleen. (C) Total number of cytokine-producing GP33–41 LCMV-specific CD8 T-cells in the spleen on day 9 post-infection. (D) Total number of cytokine-producing GP61–80 LCMV-specific CD4 T-cells in the spleen on day 9 post-infection. (E–G) Mice treated with anti-CD4 and/or anti-IFNAR1 or control antibodies were infected with 2 × 106 PFU of Cl13 and viral titers were measured in the serum and tissues at the indicated times post-infection. Viral titers in the serum were quantified by plaque assay on days 14, 21 and 40 (E) and 50 (F) in the serum. (G) Depicts viral titers in the lung, kidney and brain in CD4-depleted mice treated with isotype or anti-IFNAR1 on day 75 post-infection. *, p < 0.05; **, p < 0.01; ***, p < 0.005. Results are representative of 2 independent experiments and represent SEM from 4–5 mice per group.
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Comment in

  • Immunology. An interferon paradox.
    Odorizzi PM, Wherry EJ. Odorizzi PM, et al. Science. 2013 Apr 12;340(6129):155-6. doi: 10.1126/science.1237568. Science. 2013. PMID: 23580520 Free PMC article.

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