Comparison of Dendritic Cell Activation by Virus-Based Vaccine Delivery Vectors Emphasizes the Transcriptional Downregulation of the Oxidative Phosphorylation Pathway

Hum Gene Ther. 2019 Apr;30(4):429-445. doi: 10.1089/hum.2018.161. Epub 2019 Jan 25.

Abstract

Antigen delivery platforms based on engineered viruses or virus-like particles are currently developed as vaccines against infectious diseases. As the interaction of vaccines with dendritic cells (DCs) shapes the immunological response, we compared the interaction of a range of virus-based vectors and virus-like particles with DCs in a murine model of systemic administration and transcriptome analyses of splenic DCs. The transcriptome profiles of DCs separated the vaccine vectors into two distinct groups characterized by high- and low-magnitude differential gene expression, which strongly correlated with (1) the surface expression of costimulatory molecules CD40, CD83, and CD86 on DCs, and (2) antigen-specific T-cell responses. Pathway analysis using PANOGA (Pathway and Network-Oriented GWAS Analysis) revealed that the JAK/STAT pathway was significantly activated by both groups of vaccines. In contrast, the oxidative phosphorylation pathway was significantly downregulated only by the high-magnitude DC-stimulating vectors. A gene signature including exclusively chemokine-, cytokine-, and receptor-related genes revealed a vector-specific pattern. Overall, this in vivo DC stimulation model demonstrated a strong relationship between the levels of induced DC maturation and the intensity of T-cell-specific immune responses with a distinct cytokine/chemokine profile, metabolic shifting, and cell surface expression of maturation markers. It could represent an important tool for vaccine design.

Keywords: adenovirus; dendritic cells; modified vaccinia virus; oxidative phosphorylation; virus-based vaccine vectors; virus-like particles.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers
  • Computational Biology / methods
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism*
  • Down-Regulation
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Gene Transfer Techniques
  • Genetic Vectors / administration & dosage
  • Genetic Vectors / genetics*
  • Humans
  • Mice
  • Molecular Sequence Annotation
  • Oxidative Phosphorylation*
  • Spleen / cytology
  • Spleen / immunology
  • Transcription, Genetic*
  • Transcriptome
  • Vaccines, Virus-Like Particle / administration & dosage
  • Vaccines, Virus-Like Particle / genetics*
  • Vaccines, Virus-Like Particle / immunology*

Substances

  • Biomarkers
  • Vaccines, Virus-Like Particle