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

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

Author information

1
1 Molecular Virology Laboratory, Hellenic Pasteur Institute, Athens, Greece.
2
2 Department of Biophysics, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey.
3
3 Department of Biostatistics and Medical Informatics, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey.
4
4 Sorbonne Université, INSERM, UMRS 959, Immunology-Immunopathology-Immunotherapy (i3), Paris, France.
5
5 AP-HP, Hôpital Pitié-Salpêtrière, Biotherapy and Département Hospitalo-Universitaire Inflammation-Immunopathology-Biotherapy (i2B), Paris, France.
6
6 Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupolis, Greece.

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

PMID:
30351174
DOI:
10.1089/hum.2018.161
[Indexed for MEDLINE]

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