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, 80 (9), 4538-45

Sendai Virus Infection Induces Efficient Adaptive Immunity Independently of Type I Interferons

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Sendai Virus Infection Induces Efficient Adaptive Immunity Independently of Type I Interferons

Carolina B López et al. J Virol.

Abstract

Adaptive immunity in response to virus infection involves the generation of Th1 cells, cytotoxic T cells, and antibodies. This type of immune response is crucial for the clearance of virus infection and for long-term protection against reinfection. Type I interferons (IFNs), the primary innate cytokines that control virus growth and spreading, can influence various aspects of adaptive immunity. The development of antiviral immunity depends on many viral and cellular factors, and the extent to which type I IFNs contribute to the generation of adaptive immunity in response to a viral infection is controversial. Using two strains (Cantell and 52) of the murine respiratory Sendai virus (SeV) with differential abilities to induce type I IFN production from infected cells, together with type I IFN receptor-deficient mice, we examined the role of type I IFNs in the generation of adaptive immunity. Our results show that type I IFNs facilitate virus clearance and enhance the migration and maturation of dendritic cells after SeV infection in vivo; however, soon after infection, mice clear the virus from their lungs and efficiently generate cytotoxic T cells independently of type I IFN signaling. Furthermore, animals that are unresponsive to type I IFN develop long-term anti-SeV immunity, including CD8+ T cells and antibodies. Significantly, this memory response is able to protect mice against challenge with a lethal dose of virus. In conclusion, our results show that primary and secondary anti-SeV adaptive immunities are developed normally in the absence of type I IFN responsiveness.

Figures

FIG. 1.
FIG. 1.
Reduced virulence of SeV-C compared to SeV-52 in mice. (a to d) Luciferase activity of whole-cell lysates from NIH 3T3 cells cotransfected with a plasmid constitutively expressing Renilla luciferase and a plasmid containing firefly luciferase reporter constructs driven by either the complete IFN-β promoter (a and b), four copies of the NF-κB PRD of the IFNβ promoter (c), or three copies of the IRF3/7 PRD of the IFN-β promoter (d) and infected with SeV for 8 h (a, c, and d) or 24 h (b). p.i., postinfection. (e) Quantification of IFN-α and -β gene transcripts by quantitative real-time PCR analysis from lung tissue of C57BL/6 mice 6 h after intranasal infection with the same ID50 of SeV-52 or SeV-C. (f) Weight loss of C57BL/6 mice treated with PBS (⧫) or infected with 20 ID50 of SeV-C (•) or SeV-52 (□) (n = 5). An asterisk indicates statistical difference, with a P value of ≤0.05. (g) Virus titer in the lungs of C57BL/6 mice treated with PBS or infected with 20 ID50 of SeV-C or SeV-52. An asterisk indicates statistical difference, with a P value of ≤0.05. (h) Virus titer in the lungs of wild-type Sv129 and type I IFN receptor-deficient (KO) mice infected intranasally with the same ID50 of SeV-52 or SeV-C. Results are representative of more than three independent experiments. An asterisk indicates statistical difference, with a P value of <0.005. The double asterisk indicates a P value of 0.07. Error bars indicate standard deviations.
FIG. 2.
FIG. 2.
Primary immune response against SeV. (a) Virus titers in the lungs of wild-type Sv129 and type I IFN receptor-deficient mice infected intranasally with SeV-52. Error bars indicate standard deviations. (b and c) Analysis of DC maturation (CD86 expression) and migration (CCR7 expression) to the lung draining lymph nodes extracted at different days postinfection; cells gated on the CD11c+ cells. The filled histogram corresponds to the isotype controls. The dashed line corresponds to lymph nodes from mock-infected animals. Continuous lines correspond to lymph nodes extracted from infected animals at the indicated day postinfection (D). Results are representative of two independent experiments. (d) H-2b NP peptide tetramer staining of CD8+ T cells specific for SeV in mice lungs 7 days after infection. (e) In vivo cytotoxicity 5 days postinfection. Lysis of splenocytes pulsed with SeV peptide and labeled with a high dose of CFSE or mock-pulsed and labeled with a low dose of CFSE was evaluated by flow cytometry 18 h after infusion into the infected mice. Results are representative of more than three independent experiments. KO, type I IFN receptor-deficient mice.
FIG. 3.
FIG. 3.
Adaptive immunity against viruses inducing high and low levels of type I IFN. (a) Antibodies in the serum of C57BL/6 mice infected intranasally with the same ID50 of SeV-52 or SeV-C or treated with PBS as a control. Error bars indicate standard deviations. OD, optical density. (b) H-2b NP peptide tetramer staining of CD8+ T cells specific for SeV in mouse lungs 24 days after infection. Results from two different representative animals are shown. (c) IFN-γ in the supernatant of 4 day cultures of in vitro-restimulated splenocytes from animals infected with SeV. Error bars indicate standard deviations. (d) Cytotoxicity of in vitro-restimulated splenocytes from animals infected with SeV; cell lysis was determined using a Cr51 release assay. Results are representative of more than three independent experiments.
FIG. 4.
FIG. 4.
Type I IFN-independent development of anti-SeV adaptive immunity. (a) H-2b NP peptide tetramer staining of CD8+ T cells specific for SeV in wild-type Sv129 and type I IFN receptor-deficient mouse lungs 10 days after infection. (b) In vivo cytotoxicity 10 days postinfection. Lysis of splenocytes pulsed with SeV peptide and labeled with a high dose of CFSE or mock pulsed and labeled with a low dose of CFSE was evaluated by flow cytometry 18 h after infusion into the infected mice. Two different animals are shown. Results are representative of more than three independent experiments. ko, type I IFN receptor-deficient mice.
FIG. 5.
FIG. 5.
Long-term memory antiviral immunity is developed normally in the absence of type I IFN responsiveness. (a) H-2b NP peptide tetramer staining of CD8+ T cells specific for SeV-52 in lungs, spleen, and lymph nodes of Sv129 and type I IFN receptor-deficient mice, 120 days after infection. (b) In vivo cytotoxicity 60 days postinfection. Lysis of splenocytes pulsed with SeV peptide and labeled with a high dose of CFSE or mock pulsed and labeled with a low dose of CFSE was evaluated by flow cytometry 18 h after being infused into the infected mice. Results are representative of more than three independent experiments. (c) Antibodies in the serum of Sv129 and type I IFN receptor-deficient mice infected intranasally with the same ID50 of SeV-52 or SeV-C or treated with PBS as a control. Anti-SeV antibody was measured from the animals' serum 3 weeks after infection. Error bars indicate standard deviations. OD, optical density. (d) Weight of infected (□) or mock-infected (⧫) animals challenged 120 days after infection with a lethal dose of SeV. The asterisk indicates a P of 0.03. (e) Survival and (f) weight of Sv129 mice adoptively transferred with 5 × 106 bone marrow cells from infected (closed symbols) or PBS-treated (open symbols) animals and challenged with a lethal dose of SeV-52. Groups of four animals were used in panels d through f. ko, type I IFN receptor-deficient mice.

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