Development of interferon-stimulated gene expression from embryogenesis through adulthood, with and without constitutive MDA5 pathway activation
| Autor: | Laura Bankers, James H. Morrison, Chommanart Thongkittidilok, Caitlin M Miller, Eric M. Poeschla, Guoqi Liu |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Interferon-Induced Helicase
IFIH1 Picornavirus viruses Immunology Embryonic Development Context (language use) Mice Transgenic Picornaviridae Receptor Interferon alpha-beta Article Transcriptome 03 medical and health sciences Mice 0302 clinical medicine Downregulation and upregulation Gene expression Immunology and Allergy Animals Humans Viral Replicase Complex Proteins Disease Resistance Innate immune system biology Pathogen-Associated Molecular Pattern Molecules virus diseases Gene Expression Regulation Developmental MDA5 biology.organism_classification RNA-Dependent RNA Polymerase Immunity Innate Cell biology Mice Inbred C57BL RNA silencing RNA Viral Interferons 030215 immunology Signal Transduction |
| Zdroj: | J Immunol |
| Popis: | Pathogen-associated molecular patterns (e.g., dsRNA) activate expression of IFN-stimulated genes (ISGs), which protect hosts from infection. Although transient ISG upregulation is essential for effective innate immunity, constitutive activation typically causes harmful autoimmunity in mice and humans, often including severe developmental abnormalities. We have shown that transgenic mice expressing a picornavirus RNA-dependent RNA polymerase (RdRP) outside the viral context (RdRP mice) exhibit constitutive, MDA5-dependent, and quantitatively dramatic upregulation of many ISGs, which confers broad viral infection resistance. Remarkably, RdRP mice never develop autoinflammation, interferonopathy, or other discernible abnormalities. In this study, we used RNA sequencing and other methods to analyze ISG expression across five time points from fetal development to adulthood in wild-type and RdRP mice. In RdRP mice, the proportion of upregulated ISGs increased during development, with the most dramatic induction occurring 2 wk postnatally. The amplified ISG profile is then maintained lifelong. Molecular pathways and biological functions associated with innate immune and IFN signaling are only activated postnatally, suggesting constrained fetal responsiveness to innate immune stimuli. Biological functions supporting replication of viruses are only inhibited postnatally. We further determined that the RdRP is expressed at low levels and that blocking Ifnar1 reverses the amplified ISG transcriptome in adults. In conclusion, the upregulated ISG profile of RdRP mice is mostly triggered early postnatally, is maintained through adulthood, and requires ongoing type I IFN signaling to maintain it. The model provides opportunities to study the systems biology of innate immunity and to determine how sustained ISG upregulation can be compatible with robust health. |
| Databáze: | OpenAIRE |
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