Mutations in the spike glycoprotein of human coronavirus OC43 modulate disease in BALB/c mice from encephalitis to flaccid paralysis and demyelination

Abstract

The etiology of most neurodegenerative diseases of the central nervous system remains unknown and likely involves a combination of genetic susceptibility and environmental triggering factors. Given that exposure to numerous infectious pathogens occurs during childhood, and that some viral infections can lead to neurodegeneration and demyelination, it is conceivable that some viruses may act as triggering factors in neuropathogenesis. We have previously shown that the prototype OC43 strain of the common cold-associated human respiratory coronavirus has the capacity to infect human neuronal and glial cells and does persist in human brains. Moreover, it has neuroinvasive properties in susceptible BALB/c mice, where it leads to a chronic encephalitis with accompanying disabilities. Here, we show that mutations in the viral spike glycoprotein, reproducibly acquired during viral persistence in human neural cell cultures, led to a drastically modified virus-induced neuropathology in BALB/c mice, characterized by flaccid paralysis and demyelination. Even though infection by both mutated and wild-type viruses led to neuroinflammation, the modified neuropathogenesis induced by the mutated virus was associated with increased viral spread and significantly more CD4+ and CD8+ T-lymphocyte infiltration into the central nervous system, as well as significantly increased levels of the proinflammatory cytokine interleukin (IL)-6 and the chemokine CCL2 (monocyte chemoattractant protein [MCP]-1). Moreover, recombinant virus harboring the S glycoprotein mutations retained its neurotropism, productively infecting neurons. Therefore, interaction of a human respiratory coronavirus with the central nervous system may modulate virus and host factors resulting in a modified neuropathogenesis in genetically susceptible individuals.

Human coronaviruses: Viral and cellular factors involved in neuroinvasiveness and neuropathogenesis

“…The spike protein (S) is a large type 1 transmembrane glycosylated protein responsible for recognition of the cellular receptor used by the virus to infect a susceptible cell (Cavanagh, 1995). During infection of susceptible hosts, the S protein represents an important factor of virulence as it appears to be associated with most of the cytotoxic effects that lead to degeneration of infected cells following infection by different coronaviruses (Brison et al, , 2014Favreau et al, 2009Favreau et al, , 2012Iacono et al, 2006;Jacomy et al, 2010;Phillips et al, 1999Phillips et al, , 2002.…”

“…Making use of another mouse model, we showed that HCoV-OC43 induced immune cell infiltration and cytokine production within the mouse CNS. This immune response was significantly increased after infection by virus variants which harbor mutations in the surface viral glycoprotein (S), consequent of viral persistent infection of human neural cells (Jacomy et al, 2010), and which induce glutamate excitotoxicity (Brison et al, , 2014. The increased cytokine production following infection by the S-mutant viruses may induce direct damage to neurons (Amor et al, 2010) and/or disturb glutamate homeostasis by down-regulating the glutamate transporter GLT-1 on astrocytes that should recapture the excess of glutamate, which may generate glutamate excitotoxicity (Carmen et al, 2009) and thereby contribute to neuronal degeneration (Fig.…”

“…The increased cytokine production following infection by the S-mutant viruses may induce direct damage to neurons (Amor et al, 2010) and/or disturb glutamate homeostasis by down-regulating the glutamate transporter GLT-1 on astrocytes that should recapture the excess of glutamate, which may generate glutamate excitotoxicity (Carmen et al, 2009) and thereby contribute to neuronal degeneration (Fig. 4;Brison et al, 2011), which can be associated with hind-limb paralysis and possible demyelination Jacomy et al, 2010). The outcome of the observed degeneration of neurons may eventually be death of these essential cells.…”

“…2), before reaching the spinal cord. Infection of these essential cells induces their degeneration as observed by aberrant state of neurofilament phosphorylation (Brison et al, , 2014Jacomy et al, 2010), a situation that often leads to cell death and that could be directly induced by viral replication. Furthermore, using two model cell lines representing differentiated human neurons, we were able to demonstrate that programmed cell death (PCD) was induced after HCoV-OC43 infection (Favreau et al, 2009(Favreau et al, , 2012 and that the inhibition of viral replication was also in direct correlation with increased cell survival, suggesting that infection and production of progeny infectious viruses directly participate in the process of degeneration and eventual death of neurons.…”

Coronaviruses as Encephalitis - Inducing Infectious Agents

“…It is likely that strong microglial activation can trigger bystander damage, as they can release large amounts of cytokines and chemokines. In fact, we have recently shown that infection of susceptible mice by HCoV-OC43 induced the production of high level of numerous proinflammatory cytokines such as tumor necrosing factor (TNF)-alpha, interleukin (IL)-1 beta and IL-6, released in the CNS, as well as chemokines and strong infiltration of immune cells (Jacomy et al, 2010). This is again of particular interest since accumulating evidence show that these types of factors may influence the degree of encephalitis.…”