Perlot, T. | bioRxiv Science

bioRxiv2023

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

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.

neuroscience↗

bioRxiv2018

Ddx3x regulates B-cell development and light chain recombination in mice

The X chromosome gene, DDX3X, is an ATP-dependent RNA helicase with roles in transcription, splicing, nuclear export, and translation. Loss of function mutations in DDX3X are linked to a variety of neoplasms, including B-cell lymphoma. We find that conditional homozygous deletion (Mb1-Cre) of Ddx3x in developing mouse B cells in female mice results in a complete absence of mature peripheral B cells associated with an absolute block at the pro-B cell stage of development in the bone marrow. In male mice with Vav1-Cre or Mb1-Cre mediated hemizygous deletion of Ddx3x, there are less severe reductions in peripheral B-cell frequencies with skewing towards the marginal zone lineage, suggesting that the Y chromosome homolog Ddx3y or other male factors may partially compensate for loss of Ddx3x. Loss of Ddx3x in male mice is associated with perturbations at developmental time points linked to cell cycle arrest and immunoglobulin chain rearrangement. Mechanistically, loss of Ddx3x in pre-B cells is associated with reduced expression of the histone reader Brwd1, failure to curtail proliferation, and defective Igk rearrangement, which skews the peripheral B cell receptor repertoire toward lambda light chain usage. These data reveal that Ddx3x plays an essential role in B-cell development by supporting proliferative and epigenetic changes necessary for rearrangement of immunoglobulin genes.

immunology↗