Distinct Pulmonary Innate and Adaptive Immune Responses during the Initiation and Resolution of Natural and Breakthrough SARS-CoV-2 Infection

The evolution of pulmonary immune responses in breakthrough and natural SARS-CoV-2 infection was evaluated with sequential single-cell profiling of bronchoalveolar cells from 11 vaccinated and 8 unvaccinated patients during the acute and recovery phases of their illness. Longitudinal mapping of lung cell transcriptome, proteome, and immune receptor repertoire resolved distinct phenotypic and functional characteristics. Natural infections were characterized by a delayed type-I interferon response, with sustained proinflammatory and cytolytic signatures. Cell characteristics included inflammatory macrophages with effector and exhausted natural killer, CD8+ and CD4+ T-cell phenotypes. In contrast, breakthrough infections elicited persistence of type-I interferon response, antigen presentation, and cell-cell communication. Pulmonary epithelial cells initiated immune cell recruitment, activation, and immune modulation. Macrophages exhibited enhanced phagocytic and tissue repair features with maintenance of naive, terminally differentiated, and effector memory CD4+ T cells. Earlier differentiation trajectories characterized macrophage, CD4+ and CD8+ T cells with frequent innate and adaptive immune cross talk, promoting protective immune responses. Unique top T-cell receptor clones with higher clonal diversity were found in natural infection whereas clonal expansion was noted in breakthrough infections. These results highlight how the lung cellular microenvironment develops protection during the early and subsequent recovery from SARS-CoV-2 infection.