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TLR5 versus TLR7/8 agonist-dependent modulation of the early gene expression response to inactivated influenza virus vaccine in newborn nonhuman primates

ABSTRACT: There is an urgent need for strategies that can improve vaccine immunogenicity, especially for vulnerable populations such as newborns and young infants. Growing evidence supports Toll-Like Receptor agonists (TLRa) as potent stimulatory molecules to increase vaccine efficacy. We have previously demonstrated that the inclusion of either flagellin (TLR5a) or R848 (TLR7/8a) in an inactivated influenza virus vaccine can improve responses in newborn NHP, with R848 being superior at providing protection upon challenge. This study sought to identify early immune events induced by inactivated virus alone or adjuvanted with R848 or flagellin through scRNA-seq analysis of draining lymph nodes (dLN) isolated at 24 hours post-vaccination. Our study reveals that globally, R848 enhanced gene expression associated with B cell activation, while flagellin was a stronger modulator of T cells. Analysis of distinct lymph node populations showed that surprisingly, while APCs had a potent transcriptional response to inactivated virus, we observed minimal additional changes in transcriptional activity with addition of a TLRa. In contrast, R848 had a potent effect on cellular translation, while flagellin resulted in increased expression of type I interferon genes in B cells. All vaccines resulted in a population of T cells bearing an interferon response signature that was further modified by TLRa inclusion. R848 uniquely increased the expression of genes involved with cellular migration and inflammation in this population, while flagellin increased genes involved in vesicular trafficking, cAMP responsiveness, and calcium signaling. Together, these results suggest R848 promotes newborn B cell activation and enhanced migration/retention in the dLN. In contrast, flagellin amplifies the type I interferon signature of B cells and had broad impacts on the responding T cell population. Our findings provide new insights into the modulation of early vaccine responses in newborns following administration of inactivated influenza virus, R848 and flagellin.

ORGANISM(S): Chlorocebus aethiops

PROVIDER: GSE307304 | GEO | 2026/09/03

REPOSITORIES: GEO

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Project description:<p>Pseudorabies virus infection causes intestinal flora disorder in animals, leading to diarrhea. To explore the effect of inactivated pseudorabies vaccine immunization on pseudorabies virus infection, this study sequenced the serum metabolome and intestinal microbiota of Hu sheep, analyzed their differential expression and conducted a combined analysis. The results showed that all the Hu sheep in the vaccine immunization group survived, while those in the non-immunization group died. The expressions of quercetin, 3, 7-dimethylquercetin, 5-Methoxyindoleacetate, L-methionine, L-glutamic acid, thymine, adenine and 20-HETE were upregulated in the serum of the vaccine immunization group (P<0.05). The expressions of amifostine, hemialdehyde succinate and trehalose were down-regulated (P<0.05). The microbiota structure and abundance in the vaccine immunization group changed significantly, and the beneficial bacteria Christensenellaceae_R-7_group, Bifidobacterium, Solibacillus, and Rikenellaceae_RC9_gut_group increased. The results of the combined omics analysis showed that the changes of metabolites such as quercetin, 3, 7-dimethylquercetin, 5-Methoxyindoleacetate and adenine were positively correlated with the abundance changes of Rikenellaceae_RC9_gut_group (P<0.05); L-methionine and 20-HETE were positively correlated with adenine and Solibacillus (P<0.05); Succinate semialdehyde was significantly negatively correlated with Rikenellaceae_RC9_gut_group. The above results indicate that after inactivated pseudorabies vaccine immunization of Hu sheep, it affects metabolites (quercetin, 3, 7-dimethylquercetin, 5-Methoxyindoleacetate adenine, L-methionine and 20-HETE) by maintaining beneficial intestinal bacteria (Rikenella aceae_RC9_group and Solibacillus). Metabolites jointly regulate the generation of inflammatory mediators, influence the function of immune cells and participate in the regulation of oxidative stress, thereby exerting an immune protective effect. This study provides an important theoretical basis for a deeper understanding of the immune protection mechanism of inactivated pseudorabies vaccine.</p>

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TLR5 versus TLR7/8 agonist-dependent modulation of the early gene expression response to inactivated influenza virus vaccine in newborn nonhuman primates

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