Single‐cell landscape revealed immune characteristics associated with disease phases in brucellosis patients

Abstract A comprehensive immune landscape for Brucella infection is crucial for developing new treatments for brucellosis. Here, we utilized single‐cell RNA sequencing (scRNA‐seq) of 290,369 cells from 35 individuals, including 29 brucellosis patients from acute (n = 10), sub‐acute (n = 9), and chronic (n = 10) phases as well as six healthy donors. Enzyme‐linked immunosorbent assays were applied for validation within this cohort. Brucella infection caused a significant change in the composition of peripheral immune cells and inflammation was a key feature of brucellosis. Acute patients are characterized by potential cytokine storms resulting from systemic upregulation of S100A8/A9, primarily due to classical monocytes. Cytokine storm may be mediated by activating S100A8/A9‐TLR4‐MyD88 signaling pathway. Moreover, monocytic myeloid‐derived suppressor cells were the probable contributors to immune paralysis in acute patients. Chronic patients are characterized by a dysregulated Th1 response, marked by reduced expression of IFN‐γ and Th1 signatures as well as a high exhausted state. Additionally, Brucella infection can suppress apoptosis in myeloid cells (e.g., mDCs, classical monocytes), inhibit antigen presentation in professional antigen‐presenting cells (APCs; e.g., mDC) and nonprofessional APCs (e.g., monocytes), and induce exhaustion in CD8+ T/NK cells, potentially resulting in the establishment of chronic infection. Overall, our study systemically deciphered the coordinated immune responses of Brucella at different phases of the infection, which facilitated a full understanding of the immunopathogenesis of brucellosis and may aid the development of new effective therapeutic strategies, especially for those with chronic infection.