Mitochondrial hyperactivity and reactive oxygen species drive innate immunity to the yellow fever virus-17D live-attenuated vaccine
The yellow fever virus 17D (YFV-17D) live attenuated vaccine is considered one of the most successful vaccines ever generated associated with high antiviral immunity, yet the signaling mechanisms that drive the response in infected cells are not understood. Here, we provide a molecular understanding of how metabolic stress and innate immune responses are linked to drive type I IFN expression in response to YFV-17D infection. Comparison of YFV-17D replication with its parental virus, YFV-Asibi, and a related dengue virus revealed that IFN expression requires RIG-I-Like Receptor signaling through MAVS, as expected. However, YFV-17D uniquely induces mitochondrial respiration and major metabolic perturbations, including hyperactivation of electron transport to fuel ATP synthase. Mitochondrial hyperactivity generates reactive oxygen species (ROS) including peroxynitrite, blocking of which abrogated MAVS oligomerization and IFN expression in non-immune cells without reducing YFV-17D replication. Scavenging ROS in YFV-17D-infected human dendritic cells increased cell viability yet globally prevented expression of IFN signaling pathways. Thus, adaptation of YFV-17D for high growth imparts mitochondrial hyperactivity to meet energy demands, resulting in generation of ROS as the critical messengers that convert a blunted IFN response into maximal activation of innate immunity essential for vaccine effectiveness.
Authors
- Eric Bohrnsen (ORCID: https://orcid.org/0000-0003-4327-5242)
- Byron Shue (ORCID: https://orcid.org/0000-0003-1686-1043)
- Joseph W. Guarnieri (ORCID: https://orcid.org/0000-0001-7802-7826)
- Charles M. Rice (ORCID: https://orcid.org/0000-0003-3087-8079)
- Margaret R. MacDonald (ORCID: https://orcid.org/0000-0001-5177-2068)
- Gail L. Sturdevant (ORCID: https://orcid.org/0000-0001-9653-9008)
- Adam Hage (ORCID: https://orcid.org/0000-0001-7668-892X)
- Justin Lack (ORCID: https://orcid.org/0000-0003-0584-4010)
- Alison W. Ashbrook (ORCID: https://orcid.org/0000-0003-1114-1426)
- Benjamin Schwarz (ORCID: https://orcid.org/0000-0002-5894-953X)
- Sonja M. Best (ORCID: https://orcid.org/0000-0003-0206-297X)
- Seon-Hui Hong (ORCID: https://orcid.org/0000-0002-0746-9237)
- C. L. Larson (ORCID: https://orcid.org/0000-0002-0924-0604)
- Jeffrey G. Shannon (ORCID: https://orcid.org/0000-0003-4211-4308)
- Shelly J. Robertson (ORCID: https://orcid.org/0000-0003-3311-156X)
- Forrest Jessop (ORCID: https://orcid.org/0009-0001-5163-1457)
- Douglas C. Wallace (ORCID: https://orcid.org/0000-0002-7480-8278)
- Samantha G Muccilli
- Catharine M. Bosio (ORCID: https://orcid.org/0000-0001-9039-6341)
- Thomas Hsu
- J W Yewdell
Institutions
- National Institutes of Health (US)
- Children's Hospital of Philadelphia (US)
- Montana Emergent Technologies (United States) (US)
- Institute of Infection and Immunity (CA)
- University of Pennsylvania (US)
- Rockefeller University (US)
Publication Details
- Journal
- PLoS Pathogens
- Published
- 2025-04-21
- DOI
- https://doi.org/10.1371/journal.ppat.1012561
- Citations
- 4
- Primary Topic
- Mosquito-borne diseases and control
- Type
- article
- Field-Weighted Citation Impact
- 7.51