Neuroimmune mechanisms of coronavirus-induced lung inflammation and airway dysfunction

About This Grant

PROJECT SUMMARY The global impact of the COVID-19 pandemic has been profound, with nearly 800 million infections and seven million deaths worldwide. With the majority of fatalities resulting from respiratory failure, there is a pressing need to understand the factors that promote respiratory dysfunction following infection. The current paradigm centers on immunopathological mechanisms behind disease, but fails to incorporate how sensory neurons change during infection and contribute to the hallmark immune dysregulation and airway inflammation that characterize severe COVID-19. Airway sensory neurons are robustly activated by inflammatory mediators, pathogens and noxious irritants to modulate respiratory tone and initiate defense reflexes like cough, mucus production and bronchoconstriction. They also regulate the immune response to pathogens in the lung and become aberrantly activated during airway inflammation, thereby exacerbating reflex symptoms that contribute to morbidity. However, whether they play a role in the pathogenesis of coronavirus disease has not been studied, despite the potential to impact our understanding of airway physiology and identify new avenues for treatment. This proposal will test the following hypotheses: 1) that lung-innervating sensory neurons regulate the immune response to promote airway inflammation in coronavirus infection and 2) during infection, these cells undergo functional changes that contribute to respiratory dysfunction. Using the MHV-A59 mouse coronavirus infection model, our preliminary data support this hypothesis by demonstrating that the systemic ablation of TRPV1+ sensory neurons improves airway function while attenuating mortality and disease in infected mice. I will expand on these results by performing a specific, targeted ablation of the lung-innervating sensory neurons to elucidate their role in coronavirus disease pathology. I will determine if lung-innervating sensory neurons regulate airway inflammation by learning and performing spectral flow-cytometry to profile and quantify pulmonary immune cells, while separately measuring viral titer, neuropeptide and inflammatory cytokine concentrations in the lungs of infected, airway sensory neuron-ablated and intact mice. To understand how MHV-A59 infection modulates airway sensory neuron function to promote respiratory disease, I will acquire expertise in two-photon calcium imaging and electrophysiology to characterize their phenotypic changes in MHV-A59 infected animals. Lastly, I will measure oxygen saturation, breathing rates, respiratory mechanics and airway hyperreactivity in sensory neuron-ablated and intact mice to understand how these cells contribute to respiratory dysfunction. These studies will define the contribution of lung-innervating sensory neurons to coronavirus disease pathogenesis and lay the groundwork for discovering new treatments for respiratory disease.