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

BACKGROUND: Inhalation 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. RESULTS: To 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. CONCLUSIONS: Our 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.

No involvement of alveolar macrophages in the initiation of carbon nanoparticle induced acute lung inflammation in mice.

BACKGROUND: Carbonaceous nanoparticles (CNP) represent a major constituent of urban particulate air pollution, and inhalation of high CNP levels has been described to trigger a pro-inflammatory response of the lung. While several studies identified specific particle characteristics driving respiratory toxicity of low-solubility and low-toxicity particles such as CNP, the major lung cell type, which initiates and drives that response, remains still uncertain. Since alveolar macrophages (AM) are known to effectively phagocytose inhaled particles and play a crucial role for the initiation of pulmonary inflammation caused by invading microbes, we aimed to determine their role for sterile stimuli such as CNP by profiling the primary alveolar cell compartments of the lung. We exposed C57BL/6 mice to 20 µg CNP by intratracheal instillation and comprehensively investigated the expression of the underlying mediators during a time span of 3 to 72 h in three different lung cell populations: CD45- (negative) structural cells, CD45+ (positive) leukocytes, and by BAL recovered cells. RESULTS: Bronchoalveolar lavage (BAL) analysis revealed an acute inflammatory response characterized by the most prominent culmination of neutrophil granulocytes from 12 to 24 h after instillation, which declined to basal levels by day 7. As early as 3 h after CNP exposure 50 % of the AM revealed particle laden. BAL concentrations and lung gene expression profiles of TNFα, and the neutrophil chemoattractants CXCL1,-2 and-5 preceded the neutrophil recruitment and showed highest levels after 12 h of CNP exposure, pointing to a significant activation of the inflammation-evoking lung cells at this point of time. AM, isolated from lungs 3 to 12 h after CNP instillation, however, did not show a pro-inflammatory signature. On the contrary, gene expression analysis of different lung cell populations isolated 12 h after CNP instillation revealed CD45-, mainly representing alveolar epithelial type II (ATII) cells as major producer of inflammatory CXCL cytokines. Particularly by CD45- cells expressed Cxcl5 proved to be the most abundant chemokine, being 12 h after CNP exposure 24 (±11) fold induced. CONCLUSION: Our data suggests that AM are noninvolved in the initiation of the inflammatory response. ATII cells, which induced highest CXCL levels early on, might in contrast be the driver of acute neutrophilic inflammation upon pulmonary CNP exposure.