Transcriptomic and proteomic signatures of host NK cells delineate distinct immune states across tuberculosis infection statuses

Enrichment analyses of transcriptomic and proteomic data revealed that the NK cell-mediated cytotoxicity and apoptosis pathways were enriched in LTBI and ATB groups, whereas chemotaxis-related pathway enrichment was specific to ATB. Further analysis revealed that the expression of genes mediating the NK cell-mediated cytotoxicity signaling pathway through perforin-granzyme was upregulated in the LTBI state, whereas that of those associated with death receptors was elevated in ATB, potentially indicating a transformation of NK cell function in different TB infection states. Moreover, analysis of ATB-specific chemotaxis genes suggested that the migration of NK cells was likely to occur in the ATB state. Flow cytometry revealed an increased frequency of CD56dim NK cells and a decreased frequency of CD56bright NK cells in individuals with LTBI versus that in HCs in an independent cohort. In addition, RT-qPCR validation identified a four-biomarker combination (<i>SLC7A5</i>, <i>PDE4D</i>, <i>CXCR4</i>, and <i>SOCS3</i>) distinguishing ATB from HCs, a three-biomarker combination (<i>SLC7A5</i>, <i>PER1</i>, and <i>PDE4D</i>) differentiating LTBI from HC, and a three-biomarker combination (<i>SOCS3</i>, <i>GZMK</i>, and <i>HIST1H3B</i>) differentiating ATB from LTBI. These findings elucidate the immune clearance mechanism of NK cells in TB and provide clinically actionable biomarkers for infection staging, advancing our understanding of TB immunopathogenesis.