A large‐scale single‐cell transcriptomic atlas indicates the immune panorama of influenza A infection

Abstract Influenza A virus (IAV) infection has a wide clinical spectrum, from mild illness to life‐threatening pneumonia, yet the underlying immune determinants of disease remain poorly defined. Here, we generated a large‐scale single‐cell transcriptomic atlas from peripheral blood, profiling more than 612,010 cells from 97 individuals, including healthy controls, and patients with mild, severe, or convalescent IAV infection. Our findings uncovered a core immune dichotomy that determines clinical severity: a protective, monocyte‐centric antiviral state in mild disease versus a pathological, neutrophil‐ and myeloid‐derived suppressor cell (MDSC)‐driven hyperinflammatory state in severe infection. Severe disease was marked by a peripheral hyperinflammatory state, driven by specific monocyte and neutrophil subsets via the S100A8 / 9 /12– TLR4 / RAGE signaling axis, and was coupled with the expansion of granulocytic MDSCs that likely contribute to T cell paralysis. In contrast, mild disease was associated with a protective, monocyte‐centric response characterized by robust antiviral interferon signaling and enhanced antigen presentation. This functional divergence extends to the adaptive immune system, where mild disease was associated with CD8 + T cells displaying a balance of high cytotoxicity and regulated exhaustion. In severe illness, however, T cells become profoundly dysfunctional, exhibiting signatures of metabolic stress and apoptosis alongside the emergence of pathogenic, pro‐inflammatory regulatory T cells. Together, our atlas provides a high‐resolution immunological blueprint of human IAV infection, delineates the cellular states and pathways that govern clinical trajectories and offers a critical resource for developing host‐directed therapies.