Novel role of SARM1 mediated axonal degeneration in the pathogenesis of rabies

Abstract

Neurotropic viral infections continue to pose a serious threat to human and animal wellbeing. Host responses combatting the invading virus in these infections often cause irreversible damage to the nervous system, resulting in poor prognosis. Rabies is the most lethal neurotropic virus, which specifically infects neurons and spreads through the host nervous system by retrograde axonal transport. The key pathogenic mechanisms associated with rabies infection and axonal transmission in neurons remains unclear. Here we studied the pathogenesis of different field isolates of lyssavirus including rabies using ex-vivo model systems generated with mouse primary neurons derived from the peripheral and central nervous systems. In this study, we show that neurons activate selective and compartmentalized degeneration of their axons and dendrites in response to infection with different field strains of lyssavirus. We further show that this axonal degeneration is mediated by the loss of NAD and calpain-mediated digestion of key structural proteins such as MAP2 and neurofilament. We then analysed the role of SARM1 gene in rabies infection, which has been shown to mediate axonal self-destruction during injury. We show that SARM1 is required for the accelerated execution of rabies induced axonal degeneration and the deletion of SARM1 gene significantly delayed axonal degeneration in rabies infected neurons. Using a microfluidic-based ex-vivo neuronal model, we show that SARM1-mediated axonal degeneration impedes the spread of rabies virus among interconnected neurons. However, this neuronal defense mechanism also results in the pathological loss of axons and dendrites. This study therefore identifies a potential host-directed mechanism behind neurological dysfunction in rabies infection. This study also implicates a novel role of SARM1 mediated axonal degeneration in neurotropic viral infection.

Update on lyssaviruses and rabies: will past progress play as prologue in the near term towards future elimination?

“…For example, lyssavirus infection of neurons may result in mitochondrial dysfunction, producing oxidative stress and acute degenerative changes of neuronal processes 36 . In addition, one potential host-mediated response implicates a role for the SARM1 gene in axonal “self-destruction”, impeding viral spread but also with subsequent pathological impacts of neuronal and dendritic cell loss 37 .…”

Structural basis for SARM1 inhibition and activation under energetic stress

“…SARM1 (sterile α and HEAT/armadillo motif–containing protein; Mink et al, 2001 ) was first discovered as a negative regulator of TRIF (TIR domain–containing adaptor inducing interferon-β) in TLR (Toll-like receptor) signaling ( Carty et al, 2006 ). SARM1 was later shown to promote neuronal death by oxygen and glucose deprivation ( Kim et al, 2007 ) and viral infections ( Hou et al, 2013 ; Mukherjee et al, 2013 ; Sundaramoorthy et al, 2020 ; Uccellini et al, 2020 ), while also having a protective role against bacterial and fungal infections in Caenorhabditis elegans ( Couillault et al, 2004 ; Liberati et al, 2004 ). Subsequently, studies have demonstrated that SARM1 is also a key part of a highly conserved axonal death pathway that is activated by nerve injury ( Gerdts et al, 2013 ; Osterloh et al, 2012 ).…”

Modelling Lyssavirus Infections in Human Stem Cell-Derived Neural Cultures

“…Mouse models and primary mouse neuronal cultures have been the preferred source to investigate rabies pathogenesis in-vivo and in-vitro, respectively. These model systems have identified several key pathogenic mechanisms, which have greatly improved our understanding of rabies [5,10,[35][36][37]. However, there are ethical and practical constraints which can limit the investigation of upstream neuronal pathogenic mechanisms in living animals and in primary neurons.…”