The systemic pathogenesis of enterovirus

In recent years, EV-D68 outbreaks have been associated with severe respiratory illness and extra-respiratory complications, of which neurological complications occurred most frequently. However, how EV-D68 infection results in the development of severe disease and the underlying mechanism are largely unknown. This thesis aims to expand our knowledge on the systemic pathogenesis of EV-D68-associated disease focusing on the systemic dissemination and neurotropism of EV-D68 as well as to improve diagnostics for of EV-D68 associated CNS diseases. In Chapter 1, I discussed the different stages in the pathogenesis of EV-D68 infection – infection of the respiratory tract, systemic dissemination and infection of the CNS – based on observations in humans as well as experimental in vitro and in vivo studies. As the systemic dissemination of EV-D68 via the homogenous route is essential for the systemic spread, I explored in Chapter 2 the potential role of immune cells in the systemic disseminations in EV-D68 infection. During the 2014 outbreak, multiple clades were circulating of which subclade B1 was the most prevalent, and therefore associated with the development of neurological complications. In Chapter 3, I investigated whether the ability of EV-D68 viruses to replicate in cells of the CNS is a clade specific feature, and which viral factors are important for virus replication in vitro. Acute flaccid myelitis is the most common CNS complications associated with EV-D68 infections, while encephalitis and meningoencephalitis are infrequently reported. In Chapter 4, I investigated the cell tropism and replication efficiency of different EV-D68 isolates from before-and after-2014 in spinal motor neurons and cortical neurons derived from human pluripotent stem cells as well as the associated effect of virus infection on motor neurons. Diagnostics of EV-D68-associated CNS diseases are challenging because virus antigen or viral RNA are rarely detected in CSF. In Chapter