Ebola virus glycoprotein stimulates IL-18 dependent natural killer cell responses

Helen R Wagstaffe, Elizabeth A Clutterbuck, Viki Bockstal, Jeroen N Stoop, Kerstin Luhn, Macaya Douoguih, Georgi Shukarev, Matthew D Snape, Andrew J Pollard, Eleanor Riley, Martin R. Goodier

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Background
NK cells are activated by innate cytokines and viral ligands to kill virus-infected cells; these functions are enhanced during secondary immune responses and after
vaccination by synergy with effector T cells and virus-specific antibodies. In human
Ebola virus infection, clinical outcome is strongly associated with the initial innate
cytokine response, but the role of NK cells has not been thoroughly examined.
Methods
The novel 2-dose heterologous Adenovirus type 26.ZEBOV (Ad26.ZEBOV) and
modified vaccinia Ankara-BN-Filo (MVA-BN-Filo) vaccine regimen is safe and
provides specific immunity against Ebola glycoprotein, and is currently in phase 2 and 3 studies. Here, we analysed NK cell phenotype and function in response to Ad26.ZEBOV, MVA-BN-Filo vaccination regimen, and in response to in vitro Ebola
glycoprotein stimulation of PBMC isolated before and after vaccination.
Results
We show enhanced NK cell proliferation and activation after vaccination compared
with baseline. Ebola glycoprotein-induced activation of NK cells was dependent on
accessory cells and TLR-4-dependent innate cytokine secretion (predominantly from CD14+ monocytes) and enriched within less differentiated NK cell subsets. Optimal NK cell responses were dependent on IL-18 and IL-12, whilst IFN-γ secretion was
restricted by high concentrations of IL-10.
Conclusion

This study demonstrates the induction of NK cell effector functions early after
Ad26. ZEBOV, MVA-BN-Filo vaccination and provides a mechanism for the activation
60 and regulation of NK cells by Ebola GP.
Original languageEnglish
Pages (from-to)3936-3946
JournalJournal of Clinical Investigation
Volume130
Issue number7
Early online date21 Apr 2020
DOIs
Publication statusPublished - 1 Jul 2020

Keywords / Materials (for Non-textual outputs)

  • cytokines
  • immunology
  • innate immunity
  • NK cells
  • vaccines

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