Impact of Heightened UPR Activation on Inflammasome Responses to Influenza and Secondary Streptococcus pneumoniae Infection in Aged Lung

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Project Summary While influenza and pneumococcal infections are historically responsible for significant morbidity and mortality, a pandemic of respiratory disease by a novel coronavirus (SARS-CoV-2), resulting in the development of coronavirus disease 2019 (COVID-19), has been shown to develop in severe illness, with the highest morbidity and mortality occurring in older persons (> 65 years of age). We believe that the experiments in this Competitive Revision will expand upon our current findings in the influenza model and will provide a deeper understanding into how molecular and cellular pathways in the aged lung contribute to coronavirus pathogenesis. Based upon our preliminary findings gained by our parent R01, we hypothesize that dysregulated immune activation, in response to increased mitochondrial dysfunction and ROS production, results in overzealous pro-inflammatory signaling in response to an infectious viral agent, such as influenza or coronavirus. By establishing and dissecting a pivotal mechanistic link between cellular response pathways and inflammatory signaling in aged lung during viral infection, this research proposal has high potential to elucidate innovative regulatory pathways, expand our current understanding of age associated changes in mitochondrial homeostasis, and devise therapeutic strategies to improve morbidity and mortality in response to pathogenic stimuli. We are currently requesting two years of support to complete all of the experiments detailed in the Competitive Revision: Year 1 will focus on completion of Specific Aim 1 and Year 2 will focus on completion of Specific Aim 2. Summary and impact: Improve our understanding the balance between beneficial and harmful inflammation. It has been well established that inflammatory responses are tightly regulated, however the balance between harmful and beneficial responses to coronavirus has not been fully elucidated. Work entailed in the current proposal will examine the impact of location and magnitude of inflammatory cell infiltration and cytokine production on the development of pneumonia and ARDS in aged lung in response to coronavirus. Highlight similarities and differences between influenza and coronavirus, with a focus on the role of a pro-inflammatory immune response on disease pathogenesis in aged lung. At present, very little is known regarding the similarities and differences in pathogenesis of influenza and coronavirus. Heightened pro- inflammatory host immune responses, rather than viral virulence, can contribute to multi-organ tissue pathologies occurring in response to CRS. This work will allow us to examine the initiation and progression of immune responses in the aged lung during coronavirus infection and identify similarities and differences in host responsiveness to influenza (work on influenza is described in the Parent R01).