Nanoparticle exposure reactivates latent herpesvirus and restores a signature of acute infection

Abstract

BackgroundInhalation of environmental (nano) particles (NP) as well as persistent herpesvirus-infection are potentially associated with chronic lung disease and as both are omnipresent in human society a coincidence of these two factors is highly likely. We hypothesized that NP-exposure of persistently herpesvirus-infected cells as a second hit might disrupt immune control of viral latency, provoke reactivation of latent virus and eventually lead to an inflammatory response and tissue damage.ResultsTo test this hypothesis, we applied different NP to cells or mice latently infected with murine gammaherpesvirus 68 (MHV-68) which provides a small animal model for the study of gammaherpesvirus-pathogenesis in vitro and in vivo. In vitro, NP-exposure induced expression of the typically lytic viral gene ORF50 and production of lytic virus. In vivo, lytic viral proteins in the lung increased after intratracheal instillation with NP and elevated expression of the viral gene ORF50 could be detected in cells from bronchoalveolar lavage. Gene expression and metabolome analysis of whole lung tissue revealed patterns with striking similarities to acute infection. Likewise, NP-exposure of human cells latently infected with Epstein-Barr-Virus also induced virus production.ConclusionsOur results indicate that NP-exposure of persistently herpesvirus-infected cells – murine or human – restores molecular signatures found in acute virus infection, boosts production of lytic viral proteins, and induces an inflammatory response in the lung – a combination which might finally result in tissue damage and pathological alterations.Electronic supplementary materialThe online version of this article (doi:10.1186/s12989-016-0181-1) contains supplementary material, which is available to authorized users.

Acute Phase Response as a Biological Mechanism‐of‐Action of (Nano)particle‐Induced Cardiovascular Disease

“…A body of studies shows particle-induced induction of acute phase response in terms of increased Saa3 transcription and SAA3 release. [13,14,39,40,42,45,46,52,[91][92][93][94][95][96] Furthermore, Saa3 mRNA levels were increased within a few hours and SAA3 protein was measured by ELISA as early as 6 h after LPS instillation accumulating up to 24 h before slowly declining to base levels over a course of days. [97] (unpublished data) However, all these studies were conducted in bronchoalveolar lavage or whole lung tissue, and the responsible cell types have not yet been identified.…”

Nanoparticles increase human bronchial epithelial cell susceptibility to respiratory syncytial virus infection via nerve growth factor-induced autophagy

“…In contrast to our study with TiO 2 ‐NP, nanocarbon black did not alter cell titers of herpes virus after a 2‐h primary infection (Sattler et al. 2017). However, nanocarbon black and double‐walled carbon nanotubes did increase viral titers in alveolar macrophages or mouse lungs with a latent rather than ongoing infection (Sattler et al.…”

“…However, nanocarbon black and double‐walled carbon nanotubes did increase viral titers in alveolar macrophages or mouse lungs with a latent rather than ongoing infection (Sattler et al. 2017). Pulmonary exposure of mice to TiO 2 ‐NP 5 days prior to respiratory RSV infection increased the severity of RSV‐induced pneumonia, although lung viral titers were not significantly affected, perhaps due to the high level of viral inoculation used (Hashiguchi et al.…”

Nanomaterial Effects on Viral Infection

“…The noted increase in IAV titers could not be duplicated with a simultaneous dual exposure or by exposing the cells to the SWCNTs after infection (Sanpui et al 2014). However, in another study, DWCNTs were able to reactivate latent herpesvirus, suggesting that the infections occurred prior to NP exposure (Sattler et al 2017). There is not an abundance of evidence to suggest that classic additive, synergistic, or antagonistic toxicity occurs under any of these exposure scenarios, but this observation likely depends on the endpoints that are quantified, which have been limited.…”

“…Spherical carbon nanoparticles (Barras et al 2016) and fullerene (C60) derivatives (Shoji et al 2013) were shown to interfere with HSV-1 and IAV, respectively, whereas exposure to a single dose of TiO 2 nanoparticles exacerbated pneumonia in RSV-infected mice (Hashiguchi et al 2015a). Lastly, a more recent report showed for the first time the ability of double-walled carbon nanotubes (DWCNTs) to reactivate latent herpesvirus (MHV-68) in cells and mice (Sattler et al 2017). They also discovered that these DWCNTs could induce more pronounced effects in terms of reactivating latent virus than carbonaceous spherical nanoparticles.…”