Noncanonical Transmission of a Measles Virus Vaccine Strain from Neurons to Astrocytes

Poelaert, Katrien C. K.; Williams, Riley M.; Matullo, Christine M.; Rall, Glenn F.

Viruses, including members of the herpes-, entero-, and morbillivirus families, are the most common cause of infectious encephalitis in mammals worldwide. During most instances of acute viral encephalitis, neurons are typically the initial cell type that is infected. However, as replication and spread ensue, other parenchymal cells can become viral targets, especially in chronic infections. Consequently, to ascertain how neurotropic viruses trigger neuropathology, it is crucial to identify which central nervous system (CNS) cell populations are susceptible and permissive throughout the course of infection, and to define how viruses spread between distinct cell types. Using a measles virus (MV) transgenic mouse model that expresses human CD46 (hCD46), the MV vaccine strain receptor, under the control of a neuron-specific enolase promoter (NSE-hCD46(+) mice), a novel mode of viral spread between neurons and astrocytes was identified. Although hCD46 is required for initial neuronal infection, it is dispensable for heterotypic spread to astrocytes, which instead depends on glutamate transporters and direct neuron-astrocyte contact. Moreover, in the presence of RNase A, astrocyte infection is reduced, suggesting that nonenveloped ribonucleoproteins (RNP) may cross the neuron-astrocyte synaptic cleft. The characterization of this novel mode of intercellular transport offers insights into the unique interaction of neurons and glia and may reveal therapeutic targets to mitigate the life-threatening consequences of measles encephalitis.