Pseudorabies virus hijacks DDX3X, initiating an addictive 'mad itch' and immune suppression, to facilitate viral spread.

Cronin, S. J. F.; Tejeda, M. A.; Song, R.; Laval, K.; Cikes, D.; Ji, M.; Brai, A.; Stadlmann, J.; Novatchikova, M.; Perlot, T.; Ali, O. H.; Botta, L.; Decker, T.; Lazovic, J.; Hagelkruys, A.; Enquist, L.; Rao, S.; Koyuncu, O. O.; Penninger, J. M.

doi:10.1101/2023.05.09.539956

bioRxiv · 10.1101/2023.05.09.539956

Pseudorabies virus hijacks DDX3X, initiating an addictive 'mad itch' and immune suppression, to facilitate viral spread.

Cronin, S. J. F.·Tejeda, M. A.·Song, R.·Laval, K.·Cikes, D.·Ji, M.·Brai, A.·Stadlmann, J.·Novatchikova, M.·Perlot, T.·Ali, O. H.·Botta, L.·Decker, T.·Lazovic, J.·Hagelkruys, A.·Enquist, L.·Rao, S.·Koyuncu, O. O.·Penninger, J. M.

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Abstract

Infections with defined Herpesviruses, such as Pseudorabies virus (PRV) and Varicella zoster virus (VZV) can cause neuropathic itch, referred to as "mad itch" in multiple species. The underlying mechanisms involved in neuropathic "mad itch" are poorly understood. Here, we show that PRV infections hijack the RNA helicase DDX3X in sensory neurons to facilitate anterograde transport of the virus along axons. PRV induces re-localization of DDX3X from the cell body to the axons which ultimately leads to death of the infected sensory neurons. Inducible genetic ablation of Ddx3x in sensory neurons results in neuronal death and "mad itch" in mice. This neuropathic "mad itch" is propagated through activation of the opioid system making the animals "addicted to itch". Moreover, we show that PRV co-opts and diverts T cell development in the thymus via a sensory neuron-IL-6-hypothalamus-corticosterone stress pathway. Our data reveal how PRV, through regulation of DDX3X in sensory neurons, travels along axons and triggers neuropathic itch and immune deviations to initiate pathophysiological programs which facilitate its spread to enhance infectivity.

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Cronin, S. J. F., Tejeda, M. A., Song, R., Laval, K., Cikes, D., Ji, M., Brai, A., Stadlmann, J., Novatchikova, M., Perlot, T., Ali, O. H., Botta, L., Decker, T., Lazovic, J., Hagelkruys, A., Enquist, L., Rao, S., Koyuncu, O. O., Penninger, J. M.. 2023-05-09. Pseudorabies virus hijacks DDX3X, initiating an addictive 'mad itch' and immune suppression, to facilitate viral spread.. https://doi.org/10.1101/2023.05.09.539956

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