Human Alveolar Macrophages Detect SARS‐CoV‐2 Envelope Protein Through TLR2 and TLR4 and Secrete Cytokines in Response

Alveolar macrophages (AMs) are the most numerous immune cells of the lung and are the resident, sentinel lung immunocytes that summon trafficking immune cells to the compartment. Immune profiling of AMs from COVID-19 patients implicates AMs in the immune circuits that drive pulmonary inflammation in severe COVID-19 infection. However, little is known about human AM responses to SARS-CoV-2 proteins, such as the spike protein and envelope protein. We aimed to understand if human AMs recognize SARS-CoV-2 proteins and how they respond. We found that human AMs do not sense SARS-CoV-2 spike protein but do sense envelope protein via the pattern recognition receptors TLR2 and TLR4, secreting IL-1β, IFNγ, IL-12p70, IL-6, and TNFα in response. AMs from donors over the age of 70 years produced significantly more cytokines than those from younger patients following stimulation with SARS-CoV-2 envelope protein. AMs from current smokers had lower cytokine secretion. This is the first report of human AMs producing cytokines in response to SARS-CoV-2 proteins and the first to correlate those responses with clinical risk factors. These results may partly explain why older adults are at such high risk of severe lung inflammation in COVID-19.