期刊
JOURNAL OF INFECTIOUS DISEASES
卷 218, 期 8, 页码 1324-1335出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/infdis/jiy297
关键词
Varicella zoster virus; myelopathy; astrocytes; neurokinin-1 receptor; lamellipodia; aprepitant; rolapitant
资金
- National Institutes of Health [AG032958, NS094758, NS082228, NS093716, R21AI121528, R21CA209229]
- American Cancer Society [14-196-01]
- NATIONAL CANCER INSTITUTE [R21CA209229] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R21AI121528] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS094758, R01NS093716] Funding Source: NIH RePORTER
Background. Varicella zoster virus (VZV) can present as a myelopathy with spinal astrocyte infection. Recent studies support a role for the neurokinin-1 receptor (NK-1R) in virus infections, as well as for cytoskeletal alterations that may promote viral spread. Thus, we examined the role of NK-1R in VZV-infected primary human spinal astrocytes (HA-sps) to shed light on the pathogenesis of VZV myelopathy. Methods. Mock- and VZV-infected HA-sps were examined for substance P (subP) production, NK-1R localization, morphological changes, and viral spread in the presence or absence of the NK-1R antagonists aprepitant and rolapitant. Results. VZV infection of HA-sps induced nuclear localization of full-length and truncated NK-1R in the absence of the endogenous ligand, subP, and was associated with extensive lamellipodia formation and viral spread that was inhibited by NK-1R antagonists. Conclusions. We have identified a novel, subP-independent, proviral function of nuclear NK-1R associated with lamellipodia formation and viral spread that is distinct from subP-induced NK-1R cell membrane/cytoplasmic localization without lamellipodia formation. These results suggest that binding of a putative viral ligand to NK-1R produces a dramatically different NK-1R downstream effect than binding of subP. Finally, the NK-1R antagonists aprepitant and rolapitant provide promising alternatives to nucleoside analogs in treating VZV infections, including myelopathy.
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