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Transcriptome atlas of injection site response reveals initial mechanisms of mRNA vaccine immunity

ABSTRACT: Precise immunological mechanisms of mRNA vaccines have still not been fully elucidated, especially the initial immune responses at the injection site. Here, by constructing a single-cell atlas of injection site responses of mRNA vaccine, we show that stromal inflammatory responses and type I interferon responses dominate initial transcriptional reactions elicited by mRNA vaccines at the injection site. Tracking down the fates of the delivered mRNA revealed that injection site fibroblasts are highly enriched with the delivered mRNA, and they express IFN-β specifically in response to the mRNA component, not to the LNP. Accordingly, migratory dendritic cells highly expressing interferon stimulated genes (mDC_ISG) were found specifically in muscle and draining lymph nodes of mRNA vaccine injected mice, compared to the empty LNP injected mice. Co-administration of IFN-β and LNP robustly induced mDC_ISGs at the injection site and substantially enhanced antigen-specific CD8 T cell responses. Collectively, these data elucidate earliest mechanisms of the mRNA vaccine and highlight the underappreciated immunogenic role of the mRNA component in the mRNA vaccine.

ORGANISM(S): Mus musculus

PROVIDER: GSE239574 | GEO | 2023/12/14

REPOSITORIES: GEO

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Project description:The Infectious Hematopoietic Necrosic Virus (IHNV) DNA vaccine is based on the viral glycoprotein gene (G gene) and induces a non-specific anti-viral immune response and long-term specific immunity against IHNV in salmonid fishes. This study characterized gene expression responses associated with the early anti-viral response. Homozygous rainbow trout were injected intra-muscularly (I.M.) with vector DNA or the IHNV DNA vaccine. Gene expression at the I.M. site was evaluated using a 16,000 feature salmon cDNA microarray. Eighty different transcripts were significantly modulated in the vector DNA group while 910 transcripts were modulated in the IHNV DNA vaccinated group relative to control group. Quantitative reverse transcriptase PCR was used to examine expression of selected genes at the I.M. site and in other secondary tissues. In the localized response (I.M. site), the magnitudes of gene expression changes were higher in the vaccinate group relative to the vector DNA group for the majority of genes analyzed. At secondary systemic sites (e.g. gill, kidney and spleen) evaluated with RT-PCR of specific genes, the main difference was the up-regulation of the type I IFN-related genes in only the IHNV DNA vaccinated group. Keywords: disease vaccine response Gene expression at the site of I.M injection was evaluated 7 days post-injection in clonal rainbow trout. Gene expression was compared across three treatments, with replicate clonal rainbow trout individuals (Hot Creek strain) within each treatment. Treatments included injection with 1X PBS (control group), plasmid vector only (without IHNV G gene; hereafter referred to as vector group), and the pIHNV vaccine (vaccine group). Three clonal individuals from the control, three individuals from the vector group, and four individuals from the vaccine group were labeled with Cy3 and used for individual hybridizations to ten slides, comparing hybridization of each individual to a major reference RNA pool. The major reference pool consisted of three unhandled clonal rainbow trout and constituted a pool of RNA from the anterior kidney, spleen, liver and muscle and was labelled with Cy5. Total RNA was extracted from samples, amplified, and hybridized to 16,000 feature Atlantic salmon cDNA arrays developed by the Genomic Research for Atlantic Salmon project. Differential expression was compared among control, vector, and vaccine groups.

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Transcriptome atlas of injection site response reveals initial mechanisms of mRNA vaccine immunity

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