314
Views
12
CrossRef citations to date
0
Altmetric
Articles

Single-walled carbon nanotubes repress viral-induced defense pathways through oxidative stress

, , , , , , , , , & show all
Pages 1176-1196 | Received 07 Mar 2019, Accepted 11 Jul 2019, Published online: 27 Sep 2019
 

Abstract

Exposure of lung cells in vitro or mice to single-walled carbon nanotubes (SWCNTs) directly to the respiratory tract leads to a reduced host anti-viral immune response to infection with influenza A virus H1N1 (IAV), resulting in significant increases in viral titers. This suggests that unintended exposure to nanotubes via inhalation may increase susceptibility to notorious respiratory viruses that carry a high social and economic burden globally. However, the molecular mechanisms that contribute to viral susceptibility have not been elucidated. In the present study, we identified the retinoic acid-induced gene I (RIG-I) like receptors (RLRs)/mitochondrial antiviral signaling (MAVS) pathway as a target of SWCNT-induced oxidative stress in small airway epithelial cells (SAEC) that contribute to significantly enhanced influenza viral titers. Exposure of SAEC to SWCNTs increases viral titers while repressing several aspects of the RLR pathway, including mRNA expression of key genes (e.g. IFITs, RIG-I, MDA5, IFNβ1, CCL5). SWCNTs also reduce mitochondrial membrane potential without altering oxygen consumption rates. Our findings also indicate that SWCNTs can impair formation of MAVS prion-like aggregates, which is known to impede downstream activation of the RLR pathway and hence the transcriptional production of interferon-regulated anti-viral genes and cytokines. Furthermore, application of the antioxidant NAC alleviates inhibition of gene expression levels by SWCNTs, as well as MAVS signalosome formation, and increased viral titers. These data provide evidence of targeted impairment of anti-viral signaling networks that are vital to immune defense mechanisms in lung cells, contributing to increased susceptibility to IAV infections by SWCNTs.

Author contributions

The manuscript was prepared through contributions of all authors. TSA, JAL, NSB, HC, and CM conceived and designed the experiments. HC, STH, SER, JCL, and IVS performed the experiments. HC, IVS, and TSA analyzed the data and prepared the figures. HC, IVS and TSA wrote and revised the manuscript. All authors read and approved the final manuscript.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was funded by the National Institute of Health (R01HL114907 to TSA) and R01-DK105346 and U24-DK097209 (to MEM). A portion of this work was performed at the National High Magnetic Field Laboratory, which is supported by National Science Foundation Cooperative Agreement No. DMR-1644779 and the State of Florida. Also funding was received from National Heart, Lung, and Blood Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.