Induction of type I interferons and viral immunity

Virus-induced type I interferons (IFNα/β) are key mediators of innate immunity and important modulators of adaptive immunity. Early recognition of virus and induction of IFNα/β are important for limiting the spread of the virus.

In paper I we investigate which viral functions and what cellular pathways are required for the induction of IFNα/β We use a model RNA virus, Semliki Forest virus (SFV), to induce IFNα/β-production in vivo and in murine bone marrow-derived myeloid dendritic cells (mDC). We show that, both in vivo and in mDC, SFV induces IFNα/β production via a pathway different from signalling through toll like receptors (TLR)7/8, which has been described for the induction of IFNα/β by RNA virus in plasmacytoid DC. We conclude that events during or downstream of viral fusion, but prior to replication can activate IFNα/β-production and that, in mDC, this response is largely dependent on IRF-3.

In paper II, we show that SFV provides an adjuvant effect on antibody responses against co-administered protein antigens. The adjuvant effect of SFV is abolished in mice lacking the IFNα/β receptor (IFNR-A1-/-). In contrast, amplitude, longevity and composition of the antibody responses directed against virus-encoded antigens are intact in the absence of IFNα/β-signalling. Antibody responses against both the virus-encoded antigens and against co-administered antigens are intact in MyD88-/- and TLR3-/- mice, in agreement with the observation that these mice are capable of IFNα/β induction in response to SFV. Further, we show that rSFV-induced antibody responses are dependent on T cell help and we suggest that the absence of IFNα/β-signalling in the IFNR-A1-/- mice leads to insufficient priming of T helper cells by DC.

Our results show that virus-induced IFNα/β can act as a potent adjuvant for antibody responses against an unrelated foreign antigen present during viral infection, but that IFNα/β are not required for the induction of immune responses against virus-encoded antigens.

List of scientific papers

I. Hidmark AS, McInerney GM, Nordstrom EK, Douagi I, Werner KM, Liljestrom P, Karlsson Hedestam GB. (2005). Early alpha/beta interferon production by myeloid dendritic cells in response to UV-inactivated virus requires viral entry and interferon regulatory factor 3 but not MyD88. J Virol. 79(16): 10376-85.
https://pubmed.ncbi.nlm.nih.gov/16051830

II. Hidmark Å, Nordström EKL, Dosenovic P, Forsell MNE, Liljeström P, Karlsson Hedestam GB. (2006). IFNalpha/beta are required for the adjuvant effect of virus on co-immunized protein but not for virus-encoded antigens. [Submitted]