COVID-19 and Active Tuberculosis Exhibit Distinct Maturation-Associated Neutrophil Transcriptional Programs

Neutrophils can promote pathogen control or drive tissue-damaging inflammation, but the mechanisms that determine these divergent outcomes remain poorly defined. COVID-19 and active tuberculosis (TB) offer a purposeful comparison since both are pulmonary infections with substantial neutrophil involvement, yet differ in pathogen class, inflammatory duration, and the balance between neutrophil-associated host defense and pathology. We therefore tested whether their divergent neutrophil programs align with distinct maturation-associated transcriptional states. We integrated six publicly available whole-blood bulk RNA-sequencing datasets, comprising three COVID-19 and three active TB cohorts. A curated panel of 770 genes covered activation, degranulation, neutrophil extracellular trap (NET) formation, chemotaxis, cell surface receptors, and maturation. Study-associated variation was reduced using ComBat-Seq, and differential expression relative to disease-appropriate controls was assessed with DESeq2. Most genes changed in the same direction in both diseases, but 348 (45.2%) differed significantly in response magnitude, with 159 genes showing a stronger response in COVID-19 and 189 in TB. COVID-19 samples showed reduced expression of the maturation markers CD10 (MME) and CD16 (FCGR3A), alongside elevated expression of granule-cargo and NET-associated genes, including MPO and ELANE, consistent with a greater contribution from immature, emergency granulopoiesis-derived neutrophil populations. In contrast, TB samples showed higher maturation-associated, receptor, oxidative, and recruitment responses, consistent with a relatively mature receptor-competent neutrophil transcriptional signature. Independent COVID-19 Ward and pulmonary TB cohorts showed directional agreement for maturation and NET-associated signatures (100% and 90% concordance, respectively), while chemotaxis and select receptor and degranulation genes showed weaker reproducibility indicating that maturation represents the most consistently reproduced axis of distinction between the two diseases. Together, these findings identify maturation-associated transcription as the most consistently reproduced axis distinguishing COVID-19 from TB. These signatures provide candidate biomarkers for future studies linking neutrophil states to clinical outcomes and informing host-directed therapeutic strategies that preserve antimicrobial function while limiting immunopathology.