Influenza virus induced neuroinflammation in the olfactory sensory system and long-term anosmia

About This Grant

PROJECT SUMMARY Respiratory viral infection is a leading cause of olfactory loss. Many respiratory viruses can reach and infect the olfactory epithelium. Influenza virus can directly infect olfactory sensory neurons, and this infection not only can cause smell loss but also can increase the risk of developing other neurodegenerative diseases, such as Parkinson’s disease and dementia. While smell loss in most postviral patients is temporary, as the olfactory epithelium can regenerate, a subset of patients develop long-term loss that lasts more than several months, and for some the loss becomes permanent. Smell loss is associated with low quality of life, anxiety, and depression. The underlying mechanisms that drive long-term postviral smell loss remain poorly understood, and effective treatments for smell loss are currently lacking. Antiviral mechanisms are critical for tissue protection against viruses. However, these mechanisms can be weakened by genetic and/or environmental factors. Intriguingly, inborn errors in antiviral genes have been identified in humans and contribute to the severity of viral infections. Our hypothesis, strongly supported by our preliminary data, is that genetic errors in some antiviral genes contribute to severe, long-term post-influenza smell loss. Here we will test this hypothesis using preclinical animal models of influenza-induced smell loss. We will determine whether deficiency in antiviral pathways leads to inefficient virus clearance from the olfactory tissue and results in excessive and prolonged neuroinflammation, leading to death of olfactory sensory neurons, and ultimately damage to the olfactory sensory epithelium and the olfactory bulb, the first relay station of olfactory information in the brain. We will also investigate the molecular mechanisms contributing to neurodegeneration and the mechanisms underlying inhibition of neural regeneration in the olfactory epithelium following influenza virus infection. This research will provide the much-needed mechanistic insights into long- term smell loss after influenza virus infection and will reveal potential targets for developing neuroprotective therapies. Results from this study may also shed light on mechanisms of other neurodegenerative diseases associated with viral infections.