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

Abstract

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. IMPORTANCE Viruses are the most important cause of infectious encephalitis in mammals worldwide; several thousand people, primarily the very young and the elderly, are impacted annually, and few therapies are reliably successful once neuroinvasion has occurred. To understand how viruses contribute to neuropathology, and to develop tools to prevent or ameliorate such infections, it is crucial to define if and how viruses disseminate among the different cell populations within the highly complex central nervous system. This study defines a noncanonical mode of viral transmission between neurons and astrocytes within the brain.

Why does viral RNA sometimes persist after recovery from acute infections?

“…For example, for viruses that are assembled and released from the cell surface, mutations that limit or prevent cell surface expression of viral proteins can prevent recognition by antibodies. In the measles virus-induced late disease SSPE, virion proteins required for particle assembly at the plasma membrane (hemagglutinin, fusion, and matrix) have acquired changes that prevent cell surface expression and virion assembly but promote cell-to-cell ribonucleoprotein transfer to uninfected cells, thereby allowing continued spread of viral RNA without producing infectious virions [ 121 – 124 ]. Similar mutations have been observed in the viral RNAs from persistent CNS infections due to mumps and mouse hepatitis viruses [ 113 , 125 ].…”

Presence and Persistence of Andes Virus RNA in Human Semen

“…It is known that viruses may persist and slowly spread from cell to cell without the production of an infectious virus [44][45][46]. To establish persistent infections, viruses must avoid elimination by the immune response of the host; this may be achieved by establishing infections in immunologically privileged sites such as the testes.…”

Multiple Receptors Involved in Invasion and Neuropathogenicity of Canine Distemper Virus: A Review

“…Since neurons, which are important cell targets affected in SSPE, express neither SLAM nor nectin-4, CDV is thought to exploit a different infection mechanism that does not involve these two receptors [ 62 ]. Early research on the spread of MeV between neurons indicated that MeV adopts a trans-synaptic mode of spread and does not require CD46 expression [ 61 , 70 ]. However, viral transport across the synaptic cleft requires membrane fusion, with neurokinin-1 (NK-1)—a highly conserved protein expressed in diverse mammalian cells [ 71 ]—playing a possible key role as an MeV-F receptor.…”