The potential role of human immune cells in the systemic dissemination of enterovirus-D68

Abstract

Enterovirus-D68 (EV-D68) often causes mild respiratory infections, but can also cause severe respiratory infections and extra-respiratory complications, including acute flaccid myelitis (AFM). Systemic dissemination of EV-D68 is crucial for the development of extra-respiratory diseases, but it is currently unclear how EV-D68 viremia occurs. We hypothesize that immune cells contribute to the systemic dissemination of EV-D68, as this is a mechanism commonly used by other enteroviruses. Therefore, we investigated the susceptibility and permissiveness of human primary immune cells for different EV-D68 isolates. In human peripheral blood mononuclear cells (PBMC) inoculated with EV-D68, only B cells were susceptible but virus replication was limited. However, B cell-rich cultures, such as Epstein-Barr virus-transformed B-lymphoblastoid cell line (BLCL) and primary lentivirus-transduced B cells, were productively infected. In BLCL, neuraminidase treatment to remove α2,6- and α2,3-linked sialic acids resulted in a significant decrease of EV-D68 infected cells, suggesting that sialic acids are the functional receptor on B cells. Subsequently, we showed that dendritic cells (DCs), particularly immature DCs, are susceptible and permissive for EV-D68 infection and that they can spread EV-D68 to autologous BLCL. Altogether, our findings suggest that immune cells, especially B cells and DCs, play an important role in the development the systemic dissemination of EV-D68 during an infection, which is an essential step towards the development of extra-respiratory complications.