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Antiviral function of type I and type III interferons in the olfactory epithelium

ABSTRACT: Background: The olfactory epithelium (OE) is one of the few sites where environmental pathogens can gain direct access to the brain. Despite this vulnerable arrangement, little is known about the protective mechanisms in the OE to prevent viral infection and subsequent entry into the brain. Methods: We systematically investigated acute responses in the olfactory mucosa (OM) upon exposure to vesicular stomatitis virus (VSV) by RNA-seq. VSVs were nasally inoculated into C57BL/6 mice. OM were dissected for gene expression analysis at different time points after viral inoculation. Interferon functions were determined by comparing viral gene expression in interferon (Ifn) receptor knockout (Ifnar1-/- and Ifnlr1-/-) with wildtype OM. Results: Antiviral responses were observed as early as 24hrs post viral exposure in the OM. Amongst the rapidly upregulated transcripts observed were specific type I as well as type III Ifns and interferon stimulated genes. Genetic analyses demonstrated that both type I and type III IFN signaling are required for the suppression of viral replication in the OM. Nasal IFNb1 or IFNl2 administration effectively reduces viral load in the OM. Conclusions: OE possesses innate ability to respond and suppress viral infection. Type I and type III IFNs actively participate in the OE’s antiviral functions. Nasal IFN application effectively blocks viral replication in the OE suggesting therapeutic potential against viral insult.

ORGANISM(S): Mus musculus

PROVIDER: GSE154235 | GEO | 2023/07/03

REPOSITORIES: GEO

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Project description:This dataset details the time-dependent response of human Huh7 hepatoma cells to type I and type III IFN. Despite activating similar signaling cascades, the type I and type III interferons (IFNs) differ in their ability to antagonize viral replication. However, it is not clear whether these cytokines induce unique antiviral states, particularly in the liver, where the clinically important hepatitis B and C viruses cause persistent infection. Here, microarray-based gene expression analysis is combined with mechanistic studies of signaling pathways to dynamically characterize the transcriptional responses induced by these cytokines in Huh7 hepatoma cells and primary human hepatocytes. Type I and III IFNs differed greatly in their level of interferon-stimulated gene (ISG) induction with a clearly detectable hierarchy (IFN-M-NM-2 > IFN-M-NM-1 > IFN-M-NM-;3 > IFN-M-NM-;1 > IFN-M-NM-;2). This hierarchy resulted in widely varying numbers of differentially expressed genes when quantified using common statistical thresholds, even though individual IFNs did not appear to regulate unique sets of genes. The kinetic profiles of IFN-induced gene expression were also qualitatively similar with the important exception of IFN-M-NM-1. While stimulation with either IFN-M-NM-2 or IFN-M-NM-;s resulted in a similar long-lasting ISG induction, IFN-M-NM-1 signaling peaked early after stimulation then declined due to a negative feedback mechanism. The quantitative expression hierarchy and unique kinetics of IFN-M-NM-1 suggest different roles for individual IFNs in the immune response, and help explain previously observed differences in antiviral activity. Huh7 cells were seeded into 6-well plates at the density of 3x10^5 cells/well and cultured overnight before stimulation with either 500 U/ml of IFN-M-NM-1 or IFN-M-NM-2, or 10 ng/ml of IFN-M-NM-;1, IFN-M-NM-;2, or IFN-M-NM-;3. Total RNA was harvested and isolated at 0.5, 1, 2, 4, 6, 12 and 24 hours post-incubation using RNeasy Mini Kit (Qiagen) following the Affymetrix GeneChip protocol of the Keck Affymetrix Resource facility at Yale University. IFN incubation at each time point was performed in duplicate. All subsequent processing, hybridization to the Illumina HumanHT-12 microarray, and quality control analyses were carried out by the Yale Center for Genome Analysis using standard protocols.

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Antiviral function of type I and type III interferons in the olfactory epithelium

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