Virus–cell interactions in the induction of type 1 interferon by influenza virus in mouse spleen cells

Abstract

Inactivated influenza A virus and fixed, virus-infected cells induce type 1 interferon (IFN-a/b) production in murine splenocytes. In this study, we have explored the nature of the virus-spleen cell interaction that leads to IFN-a/b induction and the reason for the poor response to some virus strains. IFN-a/b induction by horse serum-sensitive, but not -resistant, strains of influenza virus was inhibited in the presence of horse serum, indicating that binding of the virus to sialylated cell receptors is a necessary step in the induction process. Furthermore, influenza viruses A/PR/8/34 (H1N1) and A/WS/33 (H1N1), which were poor inducers of IFN-a/b in spleen cells, were shown to have a more active neuraminidase than strains that induced higher IFN levels, and IFN-a/b induction by A/PR/8/34 (H1N1) and A/WS/33 (H1N1) was restored in the presence of a neuraminidase inhibitor. Growth of virus in different cell types altered the level of IFN-a/b induced in spleen cells by particular virus strains, suggesting that the nature of the carbohydrate moieties on the viral glycoproteins may also influence IFN-a/b induction in this system. Consistent with this notion, treatment of egg-grown virus with periodate to oxidize viral carbohydrate greatly reduced its capacity for IFN-a/b induction. Furthermore, induction of IFN-a/b was inhibited in the presence of the saccharides yeast mannan and laminarin. Together these findings indicate: (i) a requirement for interaction of the virus with sialylated receptors on the IFN-producing cell; (ii) an influence of viral carbohydrate on the response; and (iii) possible involvement of a lectin-like receptor on the IFN-producing cell in the induction of IFN-a/b or in regulation of this response. INTRODUCTIONThe type 1 interferons (IFN-a and -b) are key components of antiviral host defence and modulators of the immune system. Produced within hours of viral infection, IFN-a/b induces an antiviral state in uninfected cells (Isaacs & Lindenmann, 1957) that helps to contain spread of the virus (Muller et al., 1994). IFN-a/b also activates natural killer cells and macrophages (Biron et al., 1999;Bogdan, 2000), promotes the maturation and activation of dendritic cells (DCs) (Luft et al., 1998;Gallucci et al., 1999;), and displays potent adjuvant activity for T and B cell responses in vivo (Le Bon et al., 2001).Many cell types can produce IFN-a/b in response to virus infection. Double-stranded RNA (dsRNA) synthesized during the virus replicative cycle (Jacobs & Langland, 1996) is considered a likely trigger, since synthetic dsRNA, e.g. polyinosinic-polycytidylic acid [poly(I)?poly(C)] is known to be a potent inducer of type 1 IFN (De Clercq, 1981). A second pathway of IFN-a/b induction that is independent of virus replication or gene expression is seen in the response of certain cells of haemopoietic origin to enveloped viruses. These so-called 'natural' IFN-producing cells (IPCs), found in human and porcine peripheral blood and mouse spleen, produce type 1 IFN in response to physically and chemical...

Viral Activation of Macrophages through TLR-Dependent and -Independent Pathways

“…This implies that HSV induces IFN-␣␤ expression in macrophages mainly through a mechanism different from that observed in plasmacytoid DCs, which is the main producer of IFN-␣␤ during several viral infections (49 -51). The inability of UV-inactivated virus to induce IFN-␣␤ in certain cells like fibroblasts and macrophages is not a new observation and it is supported by recent studies using Newcastle disease virus, Sendai virus, and influenza virus (12,(52)(53)(54). The reason for this cell type specificity could be differential expression of cell surface receptors, or a different intrinsic ability to respond to extracellular stimuli.…”

“…The UV insensitive induction pathway can go through interactions between viral surface determinants and cell surface receptors, or it can be a result of viral factors released upon entry that interact with extracellular or intracellular receptors. This finding is exemplified by the ability of HSV glycoprotein D (gD) to bind mannose receptors inducing expression of IFN-␣␤ in DCs (11,12). The UV sensitive pathway is dependent on a functional viral genome (which is destroyed upon UV treatment), indicating that accumulation of viral RNA or proteins initiates this kind of induction pathway.…”

Regulation of Intestinal Dendritic Cell Migration and Activation by Plasmacytoid Dendritic Cells, TNF-α and Type 1 IFNs after Feeding a TLR7/8 Ligand

“…IFN-␣ was measured by ELISA using a rat mAb against mouse IFN-␣ (RMMA-1; PBL Biomedical Laboratories) as capture Ab and a polyclonal rabbit anti-mouse IFN-␣ (PBL Biomedical Laboratories) as detection Ab. The biological activity of IFN-␣␤ was confirmed by bioassay using a cytopathic effect reduction assay with L929 cells and cocal virus as a challenge virus, similar to that previously described (28).…”

“…Sections (5 m) were fixed in acetone, and fluorescently labeled sections were prepared and analyzed for the expression of CD103 and MHC class II as described previously (28). Where primary Abs against both CD103 and CD172a were used, both signals required amplification.…”

Mutations in Influenza Virus M1 CCHH, the Putative Zinc Finger Motif, Cause Attenuation in Mice and Protect Mice against Lethal Influenza Virus Infection

“…IFNs are considered the body's first line of innate antiviral defense (8,13,15). Type I IFNs (IFN-␣/␤) are the key cytokines produced by influenza A virus-infected epithelial cells, monocytes/macrophages, and spleen cells (5,29,39,52,54,70) and function as antiviral factors. Several studies have demonstrated that an early rise in the levels of IFN-␣, tumor necrosis factor (TNF), IL-1␣, IL-1␤, and IL-6 in bronchoalveolar lavage fluids or lung homogenates is associated with symptom development and lung pathology in influenza virus-infected mice (19,33,47,69).…”