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Updated: Aug 7, 2025
Dissecting Innate Immune Signaling in Viral Evasion of Cytokine Production
Published on: March 2, 2014
Transcriptional reprogramming of natural killer cells by vaccinia virus shows both distinct and conserved features
Delphine M Depierreux1, Geoffrey L Smith1, Brian J Ferguson1
1Department of Pathology, University of Cambridge, Cambridge, United Kingdom.
Abstract:
Natural killer (NK) cells have an established role in controlling poxvirus infection and there is a growing interest to exploit their capabilities in the context of poxvirus-based oncolytic therapy and vaccination. How NK cells respond to poxvirus-infected cells to become activated is not well established. To address this knowledge gap, we studied the NK cell response to vaccinia virus (VACV) in vivo, using a systemic infection murine model. We found broad alterations in NK cells transcriptional activity in VACV-infected mice, consistent with both direct target cell recognition and cytokine exposure. There were also alterations in the expression levels of specific NK surface receptors (NKRs), including the Ly49 family and SLAM receptors, as well as upregulation of memory-associated NK markers. Despite the latter observation, adoptive transfer of VACV-expercienced NK populations did not confer protection from infection. Comparison with the NK cell response to murine cytomegalovirus (MCMV) infection highlighted common features, but also distinct NK transcriptional programmes initiated by VACV. Finally, there was a clear overlap between the NK transcriptional response in humans vaccinated with an attenuated VACV, modified vaccinia Ankara (MVA), demonstrating conservation between the NK response in these different host species. Overall, this study provides new data about NK cell activation, function, and homeostasis during VACV infection, and may have implication for the design of VACV-based therapeutics.
Insights
This study reveals how natural killer (NK) cells respond to vaccinia virus (VACV) infection. While NK cells show activation markers, they did not protect mice, suggesting complex immune interactions for VACV-based therapies.
Area of Science:
- Immunology
- Virology
- Oncolytic Therapy
Background:
- Natural killer (NK) cells are crucial for controlling poxvirus infections.
- Their activation mechanisms upon encountering poxvirus-infected cells require further elucidation.
- NK cells are being explored for poxvirus-based oncolytic therapies and vaccination strategies.
Purpose of the Study:
- To investigate the NK cell response to vaccinia virus (VACV) infection *in vivo*.
- To understand NK cell activation, function, and homeostasis during VACV infection.
- To identify implications for designing VACV-based therapeutics.
Main Methods:
- Systemic VACV infection in a murine model.
- Analysis of NK cell transcriptional activity and surface receptor expression.
- Comparison with NK cell response to murine cytomegalovirus (MCMV) infection.
- Assessment of NK cell response in humans vaccinated with modified vaccinia Ankara (MVA).
Main Results:
- VACV infection induced broad transcriptional alterations in NK cells, indicating target recognition and cytokine signaling.
- Expression of NK cell receptors (Ly49, SLAM) and memory markers changed.
- Adoptive transfer of VACV-experienced NK cells did not protect against infection.
- Distinct NK transcriptional programs were identified for VACV compared to MCMV.
- Human and mouse NK cell transcriptional responses to VACV showed conservation.
Conclusions:
- NK cell responses to VACV are complex, involving transcriptional changes and altered receptor expression.
- Despite activation markers, NK cells did not confer protection in this model.
- Findings highlight conserved NK cell responses across species and inform the development of VACV-based therapies.
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