Project Summary COVID-19 is a pressing crisis. The responsible coronavirus, SARS-CoV-2, is highly infectious, spreads rapidly, and causes severe disease requiring hospitalization, critical care, or mechanical ventilation. However, even for SARS-CoV-2, only a minority of cases are severe. The biological factors determining who gets very ill need to be better understood. Severe COVID-19 involves pulmonary pathology demonstrating diffuse alveolar damage, hyaline membranes, and inflammatory infiltrates containing T cells and macrophages. While T cells are prominent in the diseased lung, diminished circulating T cells associates with poor outcome. Previous severe coronavirus diseases, SARS and MERS, provide mechanistic perspective. SARS and MERS also have lymphopenia and damaged lungs containing T cells and macrophages, and for these infections inhibiting T cells, antibodies, or monocyte-macrophages can diminish severity of disease. Whether, when, which, and why immune activities may be contributing to lung damage in subsets of COVID-19 patients are unclear. For many respiratory pathogens, heterotypic immunological memory is pivotal to the outcome of infection, but there are no data about whether this applies to coronaviruses. Four coronaviruses (OC43, HKU1, 229E, and NL63) circulate regularly and are among the most common causes of colds and pneumonias. The types of immune memory arising after infections with these viruses is uncertain, and whether or how heterotypic immune memory influences SARS-CoV-2 infections constitute a crucial knowledge gap. Heterotypic immune memory is helpful for fighting influenza viruses, RSV, and pneumococcus. However, pre-existing immunity could be detrimental instead and drive disease, which seems plausible for COVID-19 based on coronavirus epidemiology, immunology, and pathophysiology. We hypothesize that a recent coronavirus infection makes an individual susceptible to more severe COVID-19. We also recognize that the opposite may be true, and recent prior human coronavirus infection might instead provide heterotypic protection against SARS-CoV-2 and thereby make COVID-19 less severe. Either way, the question demands an answer. The effects of pre-existing heterotypic immunity on immune responses and lung defense during subsequent infections is the focus of the “Pneumonia Biology” NHLBI R35 award. To effectively and expeditiously study SARS-CoV-2 in containment facilities, including effects of a prior human coronavirus challenge, we created new collaborations and propose to perform studies that will be a change in scope and lead to this Competitive Revision to the R35. Whether and when an individual has been recently infected by other coronaviruses may be a major determinant of COVID-19 severity. We propose to answer this question, with studies expressly designed to minimize time needed while maximizing relevance and impact. Our goal is to provide this answer quickly, for informing and improving the medical and public health approaches to COVID-19.