Ecotropic Murine Leukemia Virus Infection of Glial Progenitors Interferes with Oligodendrocyte Differentiation: Implications for Neurovirulence

Abstract

Certain murine leukemia viruses (MLVs) are capable of inducing fatal progressive spongiform motor neuron disease in mice that is largely mediated by viral Env glycoprotein expression within central nervous system (CNS) glia. While the etiologic mechanisms and the glial subtypes involved remain unresolved, infection of NG2 glia was recently observed to correlate spatially and temporally with altered neuronal physiology and spongiogenesis. Since one role of NG2 cells is to serve as oligodendrocyte (OL) progenitor cells (OPCs), we examined here whether their infection by neurovirulent (FrCasE) or nonneurovirulent (Fr57E) ecotropic MLVs influenced their viability and/or differentiation. Here, we demonstrate that OPCs, but not OLs, are major CNS targets of both FrCasE and Fr57E. We also show that MLV infection of neural progenitor cells (NPCs) in culture did not affect survival, proliferation, or OPC progenitor marker expression but suppressed certain glial differentiation markers. Assessment of glial differentiation in vivo using transplanted transgenic NPCs showed that, while MLVs did not affect cellular engraftment or survival, they did inhibit OL differentiation, irrespective of MLV neurovirulence. In addition, in chimeric brains, where FrCasEinfected NPC transplants caused neurodegeneration, the transplanted NPCs proliferated. These results suggest that MLV infection is not directly cytotoxic to OPCs but rather acts to interfere with OL differentiation. Since both FrCasE and Fr57E viruses restrict OL differentiation but only FrCasE induces overt neurodegeneration, restriction of OL maturation alone cannot account for neuropathogenesis. Instead neurodegeneration may involve a two-hit scenario where interference with OPC differentiation combined with glial Env-induced neuronal hyperexcitability precipitates disease. IMPORTANCEA variety of human and animal retroviruses are capable of causing central nervous system (CNS) neurodegeneration manifested as motor and cognitive deficits. These retroviruses infect a variety of CNS cell types; however, the specific role each cell type plays in neuropathogenesis remains to be established. The NG2 glia, whose CNS functions are only now emerging, are a newly appreciated viral target in murine leukemia virus (MLV)-induced neurodegeneration. Since one role of NG2 glia is that of oligodendrocyte progenitor cells (OPCs), we investigated here whether their infection by the neurovirulent MLV FrCasE contributed to neurodegeneration by affecting OPC viability and/or development. Our results show that both neurovirulent and nonneurovirulent MLVs interfere with oligodendrocyte differentiation. Thus, NG2 glial infection could contribute to neurodegeneration by preventing myelin formation and/or repair and by suspending OPCs in a state of persistent susceptibility to excitotoxic insult mediated by neurovirulent virus effects on other glial subtypes.A variety of murine leukemia viruses (MLVs) are capable of inducing noninflammatory neurodegeneration upon infection of the central ne...

Rebound from Inhibition: Self-Correction against Neurodegeneration?

“…NG2 cells become altered and die in response to CasBrE-altered regulation of neuronal excitability rather than due to direct infection [64,66]. It is of interest that this cellular damage is not recognized as a damage associated molecular pattern (DAMP) signal by the innate immune system to activate a broad neuroinflammatory response as suggested by others [93].…”

“…CNS infection is most prominent in microglia and NG2 glia [11,60,63], however, infection of these two cell populations alone does not appear to be sufficient to cause disease [60]. A third glial cell type, most likely astrocytes, appears to be required for neurodegeneration, but its identity remains in question since virus expression in this cell type appears to be down-regulated upon their differentiation from glial progenitor cells [64,65]. Interestingly, infection of glial progenitor cells with either neurovirulent of non-neurovirulent ectopic viruses inhibits their differentiation into mature oligodendrocytes, however, the neurovirulent virus appears to bias differentiation towards an astrocytic fate, whereas the isogenic non-neurovirulent virus appears to suspend cells in a progenitor-like state [64].…”

“…Importantly, direct infection by CasBrE or related neurovirulent viruses is not directly cytotoxic to any glia or their progenitors, however, NG2 cells (aka, oligodendrocyte progenitor cells; OPCs) appear to be particularly vulnerable to the excitotoxic milieu of dysregulated circuits and hyperactive neurons [64,66]. NG2/OPC-induced cell damage is characterized by effacement of the cytoplasm, while largely sparing nuclear structures.…”

“…Whether NG2 cells participate in direct ionic buffering remains to be determined, but their ion channel/transporter expression profile suggests it is possible [69]. Alternatively, NG2 infection could act indirectly to affect astrocyte density, since CasBrE appears to bias glial differentiation towards astrocytes [64]. Whether differentiating astrocytes effectively buffer extracellular calcium in CasBrE-induced disease has not been addressed, since infection of these cells is not readily observable in the CasBrE model [11,60,65].…”

“…In the inferior colliculus, for example, infected microglia and NG2 cells are observed in close proximity to degenerating neurons [11,16,60,64]. Their infection rates increase alongside the increased loss of rebound activity, suggesting that glial-neuron connections might be critical to disease or its progression.…”