Advances in our understanding of the pathogenesis of rabies

Background: It has been recognized that despite severe clinical illness, the neuropathology of rabies is relatively bland with mild inflammatory changes and few degenerative changes in neurons. This has led to the concept that the underlying abnormality is neuronal dysfunction, but the precise mechanisms remain uncertain. Methods: We have evaluated neuronal structure in CVS- and mock-infected transgenic mice that express the yellow fluorescent protein. Because dorsal root ganglion (DRG) neurons are permissive for rabies virus infection in vitro, we used adult rodent DRG cultures to evaluate structural changes in the axons of CVS-infected cultures. We have assessed the cultures for a marker of lipid peroxidation with oxidative stress by immunostaining for 4-hydroxy-2-nonenal (4-HNE). Expression of NF-κB was evaluated by Western immunoblotting and immunofluorescence in DRG neurons, and the effects of an activator (ciliary neurotrophic factor [CNTF]) and an inhibitor (SN50) of NF-κB were evaluated. We also evaluated Krebs cycle enzyme activities and biochemical activities of the electron transport chain complexes. Results: In CVS-infected mice there was extensive degeneration of neuronal processes explaining the severe clinical disease. In vitro infection of DRG neurons showed prominant axonal swellings associated with 4-HNE immunostaining and good viability of the neurons, indicating rabies virus-induced oxidative stress. CNTF was highly neuroprotective for CVS-infected neurons in reducing the number of 4-HNE-labeled puncta. SN50 and CVS infection had an additive effect in producing axonal swellings, suggesting that NF-κB is neuroprotective. The fluorescent signal for p50 was quantitatively evaluated in the nucleus and cytoplasm of DRG neurons. At 24 hrs there was a significant increase in the nucleus:cytoplasm ratio, whereas at 48 and 72 hrs there was significantly reduced nuclear localization of NF-kB in CVS infection. In CVS infection Krebs cycle enzyme activities were normal, whereas Complex I and IV activities were significantly increased vs. mock infection. Conclusion: Neuronal dysfunction in rabies is associated with structural changes involving neuronal processes, which are mediated by oxidative stress. Rabies virus prevents nuclear activation of NF-κB. Mitochondrial dysfunction likely plays a role in the increased production of reactive oxygen species (ROS). Increased activity of Complex I may lead to ROS overproduction due to reverse electron transfer.

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