Identification of potential biomarkers of vaccine inflammation in mice
- Imperial College London, United Kingdom
- Max Planck Institute for Infection Biology, Germany
- Imperial College Healthcare NHS Trust, United Kingdom
- GlaxoSmithKline, United States
- GlaxoSmithKline, Italy
Abstract
Systems vaccinology approaches have been used to successfully define early signatures of the vaccine-induced immune response. However, the possibility that transcriptomics can also identify a correlate/surrogate for vaccine inflammation has not been fully explored. We have compared four licensed vaccines with known safety profiles, and three agonists of TLRs with known inflammatory potential, to elucidate the transcriptomic profile of an acceptable response to vaccination versus an inflammatory reaction. In mice, we looked at the transcriptomic changes in muscle at the injection site, the lymph node that drained the muscle and the PBMC isolated from the circulating blood from 4 hours and over the period of one week. A detailed examination and comparative analysis of these transcriptomes revealed a set of novel biomarkers reflective of inflammation after vaccination. These biomarkers are readily measurable in the peripheral blood, providing useful surrogates of inflammation, as a way to select candidates with acceptable safety profiles.
Data availability
Complete microarray data was deposited in NCBI's Gene Expression Omnibus and is accessible through GEO accession number GSE120661.
-
Identification of Biomarkers of Vaccine Reactogenicity:NCBI Gene Expression Omnibus, GSE120661.
Article and author information
Author details
Stefan HE Kaufmann
Funding
European Union Seventh Framework Programme (115308-2)
- Paul F McKay
- Deniz Cizmeci
- Yoann Aldon
- Jeroen Maertzdorf
- January Weiner
- Stefan HE Kaufmann
- David JM Lewis
- Robert A van den Berg
- Guiseppe Del Giudice
- Robin J Shattock
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: The animal studies were approved by the Ethical Review Board of Imperial College London where the experiments were carried out and work was performed in strict compliance with project and personal animal experimentation licences granted by the UK government in accordance with the Animals in Scientific Procedures Act (1986)- PPL 70-7457 Protocol #1. Animals received minimal handling and their physical condition was monitored at least twice daily. All procedures were performed under isoflurane anaesthesia when appropriate, and all efforts were made to minimise suffering. There was a detailed protocol in place, as per requirement of the humane endpoints described in the animal licence, for early euthanasia in the event of onset of illness or significant deterioration in condition. At the end of the experiment all animals were culled using a schedule 1 method and death confirmed before necropsy. Food and water were supplied ad libitum.
Copyright
© 2019, McKay et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 3,403
- views
-
- 442
- downloads
-
- 27
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Identification of potential biomarkers of vaccine inflammation in mice
eLife 8:e46149.
https://doi.org/10.7554/eLife.46149
Further reading
-
- Immunology and Inflammation
We identified a novel mouse plasmacytoid dendritic cell (pDC) lineage derived from the common lymphoid progenitors (CLPs) that is dependent on expression of Bcl11a. These CLP-derived pDCs, which we refer to as ‘B-pDCs’, have a unique gene expression profile that includes hallmark B cell genes, normally not expressed in conventional pDCs. Despite expressing most classical pDC markers such as SIGLEC-H and PDCA1, B-pDCs lack IFN-α secretion, exhibiting a distinct inflammatory profile. Functionally, B-pDCs induce T cell proliferation more robustly than canonical pDCs following Toll-like receptor 9 (TLR9) engagement. B-pDCs, along with another homogeneous subpopulation of myeloid-derived pDCs, display elevated levels of the cell surface receptor tyrosine kinase AXL, mirroring human AXL+ transitional DCs in function and transcriptional profile. Murine B-pDCs therefore represent a phenotypically and functionally distinct CLP-derived DC lineage specialized in T cell activation and previously not described in mice.
-
- Immunology and Inflammation
Van Gogh-like 2 (Vangl2), a core planar cell polarity component, plays an important role in polarized cellular and tissue morphology induction, growth development, and cancer. However, its role in regulating inflammatory responses remains elusive. Here, we report that Vangl2 is upregulated in patients with sepsis and identify Vangl2 as a negative regulator of The nuclear factor-kappaB (NF-κB) signaling by regulating the protein stability and activation of the core transcription component p65. Mice with myeloid-specific deletion of Vangl2 (Vangl2ΔM) are hypersusceptible to lipopolysaccharide (LPS)-induced septic shock. Vangl2-deficient myeloid cells exhibit enhanced phosphorylation and expression of p65, therefore, promoting the secretion of proinflammatory cytokines after LPS stimulation. Mechanistically, NF-κB signaling-induced-Vangl2 recruits E3 ubiquitin ligase PDLIM2 to catalyze K63-linked ubiquitination on p65, which serves as a recognition signal for cargo receptor NDP52-mediated selective autophagic degradation. Taken together, these findings demonstrate Vangl2 as a suppressor of NF-κB-mediated inflammation and provide insights into the crosstalk between autophagy and inflammatory diseases.
