SARM1 Depletion Slows Axon Degeneration in a CNS Model of Neurotropic Viral Infection

Abstract

Zika virus (ZIKV) is a neurotropic flavivirus recently linked to congenital ZIKV syndrome in children and encephalitis and Guillain-Barré syndrome in adults. Neurotropic viruses often use axons to traffic to neuronal or glial cell somas where they either remain latent or replicate and proceed to infect new cells. Consequently, it has been suggested that axon degeneration could represent an evolutionarily conserved mechanism to limit viral spread. Whilst it is not known if ZIKV transits in axons, we previously reported that ZIKV infection of glial cells in a murine spinal cord-derived cell culture model of the CNS is associated with a profound loss of neuronal cell processes. This, despite that postmitotic neurons are relatively refractory to infection and death. Here, we tested the hypothesis that ZIKV-associated degeneration of neuronal processes is dependent on activation of Sterile alpha and armadillo motif-containing protein 1 (SARM1), an NADase that acts as a central executioner in a conserved axon degeneration pathway. To test this, we infected wild type and Sarm1 homozygous or heterozygous null cell cultures with ZIKV and examined NAD+ levels as well as the survival of neurons and their processes. Unexpectedly, ZIKV infection led to a rapid SARM1-independent reduction in NAD+. Nonetheless, the subsequent profound loss of neuronal cell processes was SARM1-dependent and was preceded by early changes in the appearance of β-tubulin III staining. Together, these data identify a role for SARM1 in the pathogenesis of ZIKV infection, which may reflect SARM1's conserved prodegenerative function, independent of its NADase activity.

SARM1 detection in myelinating glia: sarm1/Sarm1 is dispensable for PNS and CNS myelination in zebrafish and mice

“…It has been postulated that one of the purposes of SARM1, a toll like adapter protein and remnant of the innate immune system, and the wider axon degeneration machinery is to bring about compartmentalized neurodegeneration to prevent spread of viral pathogens throughout the nervous system ( Tsunoda, 2008 ). In mouse CNS myelinating cocultures, loss of Sarm1 protects neuronal somas against infection and cell death ( Crawford et al, 2022 ). Zika virus preferentially infects oligodendroglia and astroglia in neuron/glia cocultures and causes glia cell death ( Cumberworth et al, 2017 ).…”

Abnormal Intraepidermal Nerve Fiber Density in Disease: A Scoping Review

“…Loss of IENFs is largely dependent on Wallerian degeneration and SARM1 activity [37][38][39][40]. While direct links between inflammation and SARM1 activity in the peripheral nerve are emerging [41,42], SARM1 is known to be heavily involved in responses evoked by pathogen-and damage-associated molecular patterns (DAMPs and PAMPs) [43,44]. Combined with the breadth of infectious and autoimmune diseases exhibiting IENF loss described here, this suggests interplay between pattern recognition receptors and the Wallerian degeneration pathway may contribute to axon retraction.…”

Axon Biology in ALS: Mechanisms of Axon Degeneration and Prospects for Therapy

“…Finally, the recent finding that zika virus causes SARM1-dependent neuronal death [ 9 ], along with earlier indications of similar effects with both rabies and West Nile virus [ 10 , 11 ], albeit so far by unknown mechanisms, raise the important question of whether endemic viruses could make an as-yet unrecognised contribution to neurodegenerative disorders such as ALS by acting on SARM1. At present, this can be only speculative, but since an environmental component in sporadic ALS of around 40% needs to be accounted for [ 74 ], and since some viruses including rabies and zika have indeed been associated with ALS risk and motor neuron death [ 75 , 76 , 77 ], it will be important to consider.…”

“…Although this prodegenerative role and its regulation in axons was discovered using the experimental platform of axon injury, SARM1 can kill the neuronal soma directly too, for example when it is becomes constitutively active through gain-of-function (GoF) mutation [ 5 , 6 ], or when it is activated by a toxin [ 7 , 8 ]. SARM1 also responds to some viruses in ways that are less well understood [ 9 , 10 , 11 ]. What is the evidence so far supporting a role for SARM1 in ALS, and what more do we need to know to confirm this and to understand how widespread its involvement is?…”