Mitochondrial Hyperactivity and Reactive Oxygen Species Drive Innate Immunity to the Yellow Fever Virus-17D Live-Attenuated Vaccine

Muccilli, S. G.; Schwarz, B.; Jessop, F.; Shannon, J. G.; Bohrnsen, E.; Shue, B.; Hong, S.-H.; Hsu, T.; Ashbrook, A. W.; Guarnieri, J. W.; Lack, J.; Wallace, D. C.; Bosio, C. M.; MacDonald, M. R.; Rice, C. M.; Yewdell, J. W.; Best, S. M.

doi:10.1101/2024.09.04.611167

bioRxiv · 10.1101/2024.09.04.611167

Mitochondrial Hyperactivity and Reactive Oxygen Species Drive Innate Immunity to the Yellow Fever Virus-17D Live-Attenuated Vaccine

Muccilli, S. G.·Schwarz, B.·Jessop, F.·Shannon, J. G.·Bohrnsen, E.·Shue, B.·Hong, S.-H.·Hsu, T.·Ashbrook, A. W.·Guarnieri, J. W.·Lack, J.·Wallace, D. C.·Bosio, C. M.·MacDonald, M. R.·Rice, C. M.·Yewdell, J. W.·Best, S. M.

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Abstract

The yellow fever virus 17D (YFV-17D) live attenuated vaccine is considered one of the 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 (mROS) and peroxynitrite, blocking of which abrogated 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 uniquely imparts mitochondrial hyperactivity generating mROS and peroxynitrite as the critical messengers that convert a blunted IFN response into maximal activation of innate immunity essential for vaccine effectiveness.

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Muccilli, S. G., Schwarz, B., Jessop, F., Shannon, J. G., Bohrnsen, E., Shue, B., Hong, S.-H., Hsu, T., Ashbrook, A. W., Guarnieri, J. W., Lack, J., Wallace, D. C., Bosio, C. M., MacDonald, M. R., Rice, C. M., Yewdell, J. W., Best, S. M.. 2024-09-07. Mitochondrial Hyperactivity and Reactive Oxygen Species Drive Innate Immunity to the Yellow Fever Virus-17D Live-Attenuated Vaccine. https://doi.org/10.1101/2024.09.04.611167

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