Key result
The human-isolate PRV variant hSD-1/2019 induced significantly more, longer, and thicker tunneling nanotubes than the classical Ea strain, facilitating efficient cell-to-cell viral transmission to evade neutralizing antibodies.
Why the study?
Pseudorabies virus has emerged as a causative agent of fatal human encephalitis, but its neuropathogenic mechanisms remain largely unexplored.
Pseudorabies virus utilizes tunneling nanotubes, dependent on the viral US3 protein, to facilitate cell-to-cell transmission and evade neutralizing antibodies, providing a potential therapeutic target for neuroinvasive viruses.
BACKGROUND: Pseudorabies virus (PRV), an alphaherpesvirus endemic in swine, has recently emerged as a causative agent of fatal human encephalitis, yet its neuropathogenic mechanisms remain largely unexplored. Tunneling nanotubes (TNTs) are actin-rich intercellular membrane extensions that have been found to mediate intercellular communication and facilitate the cell-to-cell transmisssion of viruses. METHODS: Immunofluorescence analysis, confocal imaging, time-lapse photography, in situ sectioning transmission electron microscopy, and scanning electron microscopy were employed to characterize the structure and function of PRV-induced TNTs in SK-N-SH cells widely utilized in neuroscience research. A cell compartment co-culture model was further constructed in this study, and the morphological differences in TNTs, as well as the corresponding viral transmission efficiency under immune pressure, were statistically analyzed and compared between different PRV strains. Additionally, we investigated the role of viral US3 in TNTs formation via proteins overexpression, gene-deleted virus construction and kinase-inactivated US3 protein expression. RESULTS: We demonstrate that PRV infection induces the extensive formation of TNTs in SK-N-SH cells. These structures act as protected conduits that facilitate efficient cell-to-cell viral transmission, enabling the virus to evade neutralizing antibodies. Critically, a human-isolate variant strain (hSD-1/2019) induced the formation of significantly more, longer and thicker TNTs than a classical PRV strain (Ea). In addition, hSD-1/2019 also exhibited more efficient viral transmission under immune pressure, providing a novel mechanism to explain the enhanced virulence of hSD-1/2019. Further investigation identified that the viral protein US3 and its kinase activity are essential for TNTs formation. However, TNTs induced by viral infection were morphologically distinct from those induced by US3 overexpression alone, suggesting that additional viral factors are required to regulate TNTs maturation and morphology. CONCLUSIONS: Our findings provide novel insights into PRV neuropathogenesis from the perspective of viral transport dynamics, and identify virus-induced intercellular conduits as a potential therapeutic target against infections of PRV and similar neuroinvasive viruses.
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Kuang et al. (2026) studied Pseudorabies virus (PRV) infection. Pseudorabies virus (PRV) variant hSD-1/2019 vs. Classical PRV strain (Ea) or uninfected cells was evaluated on Formation of tunneling nanotubes (TNTs). The human-isolate PRV variant hSD-1/2019 induced significantly more, longer, and thicker tunneling nanotubes than the classical Ea strain, facilitating efficient cell-to-cell viral transmission to evade neutralizing antibodies.
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