Single-Cell Transcriptome Profiling Reveals the Immune Dysregulation Characteristics of Mice Infected With Brucella abortus

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BACKGROUND: Brucellosis poses a significant threat to animal and human health globally. However, how Brucella subverts the immune response to establish persistent infections remains unclear. METHODS: We utilized single-cell RNA sequencing (scRNA-seq) to decipher the immune landscape of mice infected with Brucella abortus. Flow cytometry, a transgenic cell line and mouse, and antibody blockage were utilized to explore the relevant mechanisms. RESULTS: Brucella infection induced significant changes in the composition and signaling pathways of immune cells, and flow cytometry analysis further confirmed the scRNA-seq data. An in-depth analysis of macrophages, the main target cell for Brucella, demonstrated activation of type I interferon (IFN) and type II IFN signaling, tumor necrosis factor production, diverse cell deaths, etc. Specifically, Vir-2308 Brucella infection induced IFN-β expression, primarily originating from macrophages. In vitro, a significantly lower level of intracellular Brucella survival was observed in ifnar1-/- macrophages. In vivo, ifnar1 genetic deficiency rendered the mice less susceptible to Brucella challenge resulting in a lower bacterial load and higher levels of macrophages and neutrophils. Interestingly, Brucella infection induced a dramatic reduction of NK cells along with the upregulation of CD94:NKG2A, one typical immune checkpoint module of NK cells. Further blockage of the NKG2A receptor in mice significantly reduced the bacterial load in the tissues, concurrent with a higher ratio of mature dendritic cells and a lower proportion of B cells. CONCLUSIONS: scRNA-seq revealed that Brucella infection significantly alters the immune microenvironment in mice, providing insight into a better understanding of brucellosis pathogenesis and the immune evasion strategies of this sophisticated pathogen.

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