Single‐Cell Transcriptomic Analysis of the Immune Response to COVID‐19 and Tuberculosis Coinfection

The immune characteristics and pathological mechanisms of COVID-19 and tuberculosis coinfection are not well understood. Single-cell RNA sequencing has emerged as a powerful tool for dissecting complex immune responses and cellular interactions in infectious diseases. Here, we employed scRNA-seq, combined with laboratory examinations and clinical observations, to elucidate potential mechanisms of immunopathology and protective immunity in coinfected patients. Substantial alterations in immune cell populations in patients with severe coinfection were observed, characterized by severe lymphopenia and massive expansion of myeloid cells. Lymphocytopenia may have resulted from lymphocyte apoptosis and migration. Systemic upregulation of S100 family proteins, mainly released by classical monocytes, might contribute to inflammatory cytokine storm via <i>S100-TLR4</i>-<i>MyD88</i> signaling pathway in severely coinfected patients. Myeloid cells may contribute to immune paralysis in severe cases through expansion of myeloid-derived suppressor cells and dysregulated dendritic cell function. The immune landscape of T cells in severe patients were featured by dysregulated Th1 response, widespread exhaustion and increased cytotoxic, apoptosis, migration and inflammatory states. We observed increased plasma cells and overexpression of B-cell-activation-related pathways in severe patients. Together, we provide a comprehensive atlas illustrating the immune response to coinfected patients at the single-cell resolution and highlight mechanisms of pathogenesis in severe patients.