A Large-Scale Single-Cell Atlas Reveals the Peripheral Immune Panorama of Bacterial Pneumonia

<b>Rationale:</b> Bacterial pneumonia poses a substantial global health burden; yet, the immunological mechanisms driving disease pathogenesis and resolution are incompletely understood. <b>Methods:</b> We generated a large-scale single-cell transcriptomic atlas of peripheral blood immune cells from 100 individuals: 39 with severe bacterial pneumonia, 31 with mild disease, and 30 healthy control subjects. <b>Objectives:</b> Integrating single-cell RNA sequencing with clinical and molecular data revealed profound remodeling of the peripheral immune landscape across disease severities. <b>Measurements and Main Results:</b> Severe pneumonia was characterized by lymphopenia and monocytosis, accompanied by distinct shifts in T cell, B cell, and myeloid cell subset composition. Classical monocytes emerged as central orchestrators of the cytokine storm observed in severe cases, displaying elevated expression of proinflammatory genes (e.g., <i>S100A8/9/12</i>) and enhanced TLR4-MYD88 signaling. Exhaustion of innate-like CD8⁺ T cells, marked by upregulation of canonical inhibitory receptors, was a hallmark of severe disease. In contrast, mild pneumonia exhibited robust CD8⁺ T effector and helper memory cell activation, together with effective humoral immunity, evidenced by plasma cell expansion and coordinated T follicular helper cell-B cell interactions. B cells in mild cases showed enhanced antigen recognition, BCR signaling, and costimulatory gene expression, whereas those in severe cases displayed signs of dysfunction. Myeloid cell alterations in severe pneumonia included increased monocytic myeloid-derived suppressor cells and nonclassical monocytes, contributing to immunosuppression and complement overactivation, respectively. <b>Conclusions:</b> This high-resolution atlas of peripheral immune responses in bacterial pneumonia identifies key cellular and molecular drivers of disease severity, providing potential therapeutic targets for immunomodulation and improved outcomes.