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An mRNA vaccine induces antimycobacterial immunity by activating DNA damage repair and autophagy

ABSTRACT: Effective vaccines are urgently needed for the control of tuberculosis (TB). Here, we report that a mRNA TB vaccine is highly effective and exhibits both prophylactic and therapeutic activities in the zebrafish model of TB. Adult zebrafish immunized with the mRNA vaccine survived significantly longer than the DNA vaccine after Mycobacterium marinum challenge, and post-infection treatment with the mRNA vaccine drastically reduced the bacterial burden. The mRNA vaccine activated multiple DNA break repair systems that are essential for the normal development and function of adaptive immunity, but not the canonical DNA damage responses that promote cell death, demonstrating a profound connection between DNA damage repair and the activation of immune responses under physiological processes of immunization. Remarkably, the mRNA vaccine induced autophagy in granulomas, coinciding with bacterial killing and cell survival. Collectively, these findings demonstrate that the mRNA vaccine elicits potent innate and adaptive immunity, conferring effective host protection against mycobacterial challenge.

ORGANISM(S): Danio rerio

PROVIDER: GSE269547 | GEO | 2025/01/08

REPOSITORIES: GEO

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Project description:Simple cost-effective bacterins are the earliest and most successfully used commercial vaccines in fish. In particular, those prepared from Yersinia ruckeri have proven effective at controlling Enteric Red Mouth Disease (ERM) and yersiniosis in rainbow trout and Atlantic salmon, respectively. However, the emergence of outbreaks of ERM caused by atypical biotypes of Y. ruckeri and reports of vaccine failure resulting in mass mortality of hatchery Atlantic salmon has reinvigorated interest in vaccines against fish bacterial diseases. Therefore the objective of this study was to identify surrogates of protection against yersiniosis using cDNA microarray to characterise the response of host genes in the gills of unvaccinated and vaccinated Atlantic salmon challenged with Y. ruckeri. Differentially expressed genes were identified using two-way ANOVA and restricted to those with >2.5-fold change at P<0.05. Using cDNA microarray we identified the expression of 6 genes in response to infection and 4 genes associated with the protective host response to yersiniosis. Analysis by real-time PCR confirmed that three immunologically relevant genes, namely a cathelicidin (47-fold) and a C-type lectin (19-fold) increased in response to yersiniosis. Including collagenase (17-fold increase), an important tissue remodelling and repair enzyme, these genes represent 3 of 6 non-protective and/or pathological responses to yersiniosis. Genes associated with the protective host response included an immunoglobulin gene and a selenoprotein that showed significant fold changes (15-fold increases each), highlighting the importance of antibody-mediated protection against yersiniosis. These findings provide much needed knowledge of the host-pathogen interaction in response to bacterial infection and immunisation in fish. Significantly, we identified a transcriptional biosignature consisting of predominantly immune-relevant genes (14 up and 3 down-regulated) in the gills of Atlantic salmon after immersion vaccination and before bacterial challenge. This biosignature may be used as a surrogate of protection and therefore as a predictor of vaccine success against yersiniosis. 36 microarray slides representing 6 individual fish (biological replicates) at 0 h (pre-challenge), 8 h, and 72 h post-challenge from both vaccinated and unvaccinated fish. Two-colour array using sample cDNA labelled with Cy5 and a common reference aRNA labelled with Cy3 hybridized to each slide.

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An mRNA vaccine induces antimycobacterial immunity by activating DNA damage repair and autophagy

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