Neuroinflammation resulting from covert brain invasion by common viruses - a potential role in local and global neurodegeneration.

Summary Neurodegenerative diseases are a horrendous burden for their victims, their families, and society as a whole. For half a century scientists have pursued the hypothesis that these diseases involve a chronic viral infection in the brain. However, efforts to consistently detect a specific virus in brains of patients with such diseases as Alzheimer's or multiple sclerosis have generally failed. Neuropathologists have become increasingly aware that most patients with neurodegenerative diseases demonstrate marked deterioration of the brain olfactory bulb in addition to brain targets that define the specific disease. In fact, the loss of the sense of smell may precede overt neurological symptoms by many years. This realization that the olfactory bulb is a common target in neurodegenerative diseases suggests the possibility that microbes and/or toxins in inhaled air may play a role in their pathogenesis. With regard to inhaled viruses, neuropathologists have focused on those viruses that infect and kill neurons. However, a recent study shows that a respiratory virus with no neurotropic properties can rapidly invade the mouse olfactory bulb from the nasal cavity. Available data suggest that this strain of influenza is passively transported to the bulb via the olfactory nerves (mechanism unknown), and is taken up by glial cells in the outer layers of the bulb. The infected glial cells appear to be activated by the virus, secrete proinflammatory cytokines, and block further spread of virus within the brain. At the time that influenza symptoms become apparent (15h post-infection), but not prior to symptom onset (10h post-infection), proinflammatory cytokine-expressing neurons are increased in olfactory cortical pathways and hypothalamus as well as in the olfactory bulb. The mice go on to die of pneumonitis with severe acute phase and respiratory disease symptoms but no classical neurological symptoms. While much remains to be learned about this intranasal influenza-brain invasion model, it suggests the hypothesis that common viruses encountered in our daily life may initiate neuroinflammation via olfactory neural networks. The numerous viruses that we inhale during a lifetime might cause the death of only a few neurons per infection, but this minor damage would accumulate over time and contribute to age-related brain shrinkage and/or neurodegenerative diseases. Elderly individuals with a strong innate inflammatory system, or ongoing systemic inflammation (or both), might be most susceptible to these outcomes. The evidence for the hypothesis that common respiratory viruses may contribute to neurodegenerative processes is developed in the accompanying article.