Abstract
Trans-neuronal viruses are frequently used as neuroanatomical tools for mapping neuronal circuits. Specifically, recombinant one-step rabies viruses (RABV) have been instrumental in the widespread application of viral circuit mapping, as these viruses have enabled labs to map the direct inputs onto defined cell populations. Within the neuroscience community, it is widely believed that RABV spreads directly between neurons via synaptic connections, a hypothesis based principally on two observations. First, the virus labels neurons in a pattern consistent with known anatomical connectivity. Second, few glial cells appear to be infected following RABV injections, despite the fact that glial cells are abundant in the brain. However, there is no direct evidence that RABV can actually be transmitted through synaptic connections. Here we review the immunosubversive mechanisms that are critical to RABV’s success for infiltration of the central nervous system (CNS). These include interfering with and ultimately killing migratory T cells while maintaining levels of interferon (IFN) signaling in the brain parenchyma. Finally, we critically evaluate studies that support or are against synaptically-restricted RABV transmission and the implications of viral-host immune responses for RABV transmission in the brain.
Highlights
Trans-Neuronal Viruses as Neuroanatomical ToolsViruses are an integral component of the modern neuroscientist’s toolkit for neuroanatomical mapping
This study found that astrocytes but not neurons, microglia, or macrophages were the main producers of IFN-β in response to the direct intracranial infection of the neurotropic viruses Theiler’s murine encephalomyelitis virus (TMEV) or rabies viruses (RABV), or intranasal infection using vesicular stomatitis virus (VSV) or RABV
Since maintaining the health of infected cells appears to be a critical factor that determines virulence (Morimoto et al, 1999; Préhaud et al, 2003; Fu and Jackson, 2005; Sarmento et al, 2005; Dietzschold et al, 2008; Lafon, 2011), this mode of transmission would likely be positively selected over time. This means that, contrary to the hypothesis that RABV transmits directly between synaptically-connected cells in order to avoid glial cells and immune detection, RABV may spread to astrocytes (Figure 2), and this infection may be a way to increase the survival of infected neurons and increase the likelihood that the virus makes it to the salivary gland and new hosts
Summary
Trans-Neuronal Viruses as Neuroanatomical ToolsViruses are an integral component of the modern neuroscientist’s toolkit for neuroanatomical mapping. We highlight mechanisms by which IFN-producing cells are stimulated, and postulate that: (1) RABV and perhaps other neurotropic viruses may not transmit exclusively through synapses and instead regularly enter glial cells such as astrocytes; and (2) this lack of synaptic specificity has likely been selected for as a mechanism of eliciting low-level IFN response to evade immune cell mediated clearance.
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