54 Impact of Carbon Nanoparticle–Triggered Gammaherpesvirus Reactivation on Lung Immunity and Diseases

Abstract

Abstract Inhalation of environmental particles and herpesvirus infection are ubiquitous in our society. Herpesviruses persist lifelong in the host in a latent state, which can be exited by stress-induced reactivation with production of lytic virus. Our previous investigations show that pulmonary exposure to carbon nanoparticles (CNP) triggers reactivation of latent murine gammaherpesvirus 68 (MHV-68) in mouse lungs, mainly localizing to CD11b+ infiltrating macrophages and dependent on p38 MAPK signaling. Furthermore, we observed that a two-time repeated CNP administration to latently infected mice resulted in alveolar damage leading to progressive emphysema. However, the underlying adverse mechanisms causing alveolar damage and the corresponding cell communication upon CNP exposure in latently infected lungs is still unclear. To investigate this, we developed a 3D lung organoid culture from primary murine epithelial cells in combination with persistently MHV-68 infected macrophages. This model enables us to detect reactivation and cytokine release upon CNP exposure, and to gain insights into the cellular communication of epithelial cells and macrophages, to understand the mechanisms underlying reactivation-triggered damage. In parallel, adverse effects of this second hit scenario on the alveolar epithelium and subsequent disease development get investigated in vivo. Latently infected mice are exposed to CNP up to 5 times, and virus reactivation and further epithelial damage is analyzed. By uncovering molecular mechanisms underlying the adverse effects and elucidating the communication occurring in vitro and in vivo we want to identify potential targets to prevent exacerbation of lung diseases caused by these two omnipresent factors, herpesvirus infection and ambient particle exposure.