Neutrophil Maturation Emerges as the Clearest Divider Between COVID-19 and Active Tuberculosis
COVID-19 and active tuberculosis both recruit neutrophils into the lung, yet the transcriptional programs attached to those cells are not the same. In a preprint analysis of six publicly available whole-blood bulk RNA-sequencing cohorts, investigators compared three COVID-19 datasets with three active TB datasets and asked whether the immune response in each disease maps to different stages of neutrophil maturation. The answer was yes, and the strongest signal centered on maturation state rather than on any single inflammatory pathway.
The analysis used a curated panel of 770 genes spanning activation, degranulation, neutrophil extracellular trap formation, chemotaxis, cell-surface receptors, and maturation. Study-related batch effects were reduced with ComBat-Seq, and differential expression versus disease-appropriate controls was assessed with DESeq2. Across the combined comparison, most genes moved in the same direction in both diseases, but 348 genes, or 45.2%, differed significantly in response magnitude. Of those, 159 showed a stronger response in COVID-19 and 189 in TB.
One sentence captures the biology cleanly: COVID-19 leaned toward an immature, NET-prone neutrophil program, while active TB retained a more mature, receptor-competent signature.
Immature COVID-19 Signatures Versus Receptor-Rich TB Profiles
The COVID-19 cohorts showed reduced expression of the maturation markers CD10 (MME) and CD16 (FCGR3A), alongside higher expression of granule-cargo and NET-associated genes such as MPO and ELANE. In practical immunologic terms, that pattern fits with emergency granulopoiesis, in which the marrow releases less mature neutrophil populations into circulation during severe systemic stress. Those cells can be effective at rapid antimicrobial deployment, but they are also more likely to carry the machinery for collateral tissue injury, especially when NET formation becomes excessive.
TB told a different story. The active tuberculosis cohorts showed higher maturation-associated, receptor, oxidative, and recruitment responses. The more mature profile suggests a population better equipped for receptor-mediated sensing and coordinated trafficking, rather than the abrupt release of immature cells seen in severe viral inflammation. In pulmonary infection, this distinction matters because neutrophil function is not a binary of “helpful” or “harmful”; it is a balance between microbial containment, directed migration, oxidative killing, and inflammatory spillover into alveolar tissue.
The transcriptional divergence also fits the biology of the two infections. SARS-CoV-2 can trigger acute systemic inflammation over a compressed time course, a setting in which emergency myelopoiesis and immature neutrophil release are common. Tuberculosis, by contrast, is a chronic mycobacterial disease shaped by prolonged host-pathogen interaction, with immune pressure building over time and selecting for more sustained receptor-driven responses. Those different timelines create different cellular inventories in blood, and the gene-expression data reflect that split.
Reproducibility Favored Maturation and NET-Associated Genes
The investigators did not stop at the pooled analysis. They also tested whether the same directional patterns appeared in independent cohorts, including COVID-19 Ward and pulmonary TB datasets. Maturation-associated signatures reproduced with 100% directional concordance, and NET-associated signatures reached 90% concordance. Chemotaxis genes, selected receptors, and some degranulation genes were less reproducible, which places maturation at the top of the hierarchy for cross-study consistency.
That result is important because transcriptomic signals often fragment when moved from one dataset to another. Here, the maturation axis held together across independent cohorts despite differences in study design, sampling context, and disease setting. The recurrent signal suggests that neutrophil maturation state is not a peripheral observation; it may be one of the most stable molecular contrasts between these two pulmonary infections.
The NET signal deserves special attention. NETs can trap pathogens, but they also expose host tissue to proteases, oxidants, and extracellular DNA structures that can amplify lung injury. In COVID-19, elevated MPO and ELANE expression alongside reduced CD10 and CD16 points to a neutrophil population primed for heightened effector activity without the full regulatory maturity seen in TB. In TB, the stronger receptor and oxidative signature suggests cells prepared for persistent immune engagement rather than abrupt emergency release.
What These Signatures Can and Cannot Do Yet
The study does not establish clinical thresholds, and it does not claim that these transcriptional programs can already classify individual patients at the bedside. It does, however, define a biologically coherent axis that could be useful in future biomarker work: maturation-linked transcriptional state. If future studies connect these signatures to severity, lung injury, treatment response, or outcomes, they could help separate protective neutrophil activity from the kind of dysregulated inflammation that worsens disease.
There is also a therapeutic implication buried in the data. Host-directed strategies in both COVID-19 and TB have to preserve antimicrobial defense while limiting immunopathology. A neutrophil program marked by immaturity and exaggerated NET gene expression may call for a different intervention strategy than one dominated by mature receptor signaling and oxidative responses. The right treatment target could differ depending on whether the dominant problem is emergency granulopoiesis, pathologic degranulation, excessive NET formation, or sustained recruitment.
The preprint status matters here. These findings have not yet undergone peer review, and the analysis relies on bulk whole-blood RNA sequencing rather than single-cell profiling, so the exact cellular source of each transcript cannot be resolved with perfect precision. Even so, the pattern is internally consistent: maturation-associated transcription is the most reproducible molecular distinction separating COVID-19 from active tuberculosis. Future work will need to test whether that distinction tracks with clinical severity, microbiologic burden, or response to therapy, and whether it can be translated into a practical biomarker rather than remaining a descriptive immune signature.