Programming Innate Memory Responses to promote host defense against SARS-CoV-2 Pneumonia

Globally, respiratory infections cause more than 4 million deaths per year, with influenza virus (e.g. H1N1) and tuberculosis (TB) being major causes of mortality and morbidity. While viral pneumonias remain a global threat, the COVID-19 pandemic underlines the need for developing novel therapies that protect against emerging viruses. Host survival during infection in vital organs, such as the lung, requires a delicate balance between host resistance (eliminating the pathogens), and disease tolerance (minimizing collateral tissue damage). In fact, most pulmonary-virus related deaths (1-5%) result from a dysregulated host immune response to the virus (Immunopathology) rather than the cytopathic effects of the virus itself. Thus, it can be argued that pulmonary viruses are not the main threat; rather, it is the host's own immune-inflammatory response that jeopardizes host fitness/survival. However, the mechanism of how the immune system becomes dysregulated to the point of causing such massive immunopathology and how we can reverse this pathological process are currently not well understood. This proposal aims to address this fundamental question and design a therapeutic approach to prevent the severe COVID-19 disease.