Murine interferon lambdas (type III interferons) exhibit potent antiviral activity in vivo in a poxvirus infection model.
Human interferon lambdas (IFN-lambdas) (type III IFNs) exhibit antiviral activity in vitro by binding to a receptor complex distinct from that used by type I and type II IFNs, and subsequent signalling through the Janus kinase signal transducers and activators of transcription (STAT) pathway. However, evidence for a function of type III IFNs during virus infection in vivo is lacking. Here, the expression of murine IFN-lambdas by recombinant vaccinia virus (VACV) is described and these proteins are shown to have potent antiviral activity in vivo. VACV expressing murine IFN-lambda2 (vIFN-lambda2) and IFN-lambda3 (vIFN-lambda3) showed normal growth in tissue culture and expressed N-glycosylated IFN-lambda in infected cell extracts and culture supernatants. The role that murine IFN-lambdas play during virus infection was assessed in two different mouse models. vIFN-lambda2 and vIFN-lambda3 were avirulent for mice infected intranasally and induced no signs of illness or weight loss, in contrast to control viruses. Attenuation of vIFN-lambda2 was associated with increases in lymphocytes in bronchial alveolar lavages and CD4+ T cells in total-lung lymphocyte preparations. In addition, vIFN-lambda2 was cleared more rapidly from infected lungs and, in contrast to control viruses, did not disseminate to the brain. Expression of IFN-lambda2 also attenuated VACV in an intradermal-infection model, characterized by a delay in lesion onset and reduced lesion size. Thus, by characterizing murine IFN-lambdas within a mouse infection model, the potent antiviral and immunostimulatory activity of IFN-lambdas in response to poxvirus infection has been demonstrated.
Bartlett
Nathan W
NW
Department of Virology, Faculty of Medicine, Imperial College London, Norfolk Place, London W2 1PG, UK.
Buttigieg
Karen
K
Department of Virology, Faculty of Medicine, Imperial College London, Norfolk Place, London W2 1PG, UK.
Kotenko
Sergei V
SV
Department of Biochemistry and Molecular Biology, UMDNJ-New Jersey Medical School, Newark, USA.
Smith
Geoffrey L
GL
Department of Virology, Faculty of Medicine, Imperial College London, Norfolk Place, London W2 1PG, UK.
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D004195:Disease Models, Animal; D015870:Gene Expression; D007372:Interferons / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D018655:Lymphocyte Count; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010802:Phylogeny; D011213:Poxviridae Infections / Q000276:immunology* / Q000473:pathology; D016865:Reassortant Viruses / Q000276:immunology; D012867:Skin / Q000473:pathology; D014616:Vaccinia virus / Q000276:immunology
C000602567:interferon-lambda3, mouse; D007372:Interferons