Monocyte-Linked Complement Remodeling Correlates With Tuberculosis Disease Activity and Severity

Tuberculosis disease progression is shaped not solely by pathogen burden but also by host inflammatory remodeling, according to research evaluating peripheral complement dysregulation as a host-response program associated with disease activity, disease severity, and patient clinical outcomes. To investigate whether systemic complement alterations track active tuberculosis pathology, the investigators implemented a multi-platform study design combining molecular, cellular, and clinical measures. The research integrated publicly available transcriptomic datasets derived from peripheral blood mononuclear cells with targeted clinical quantitative reverse transcription polymerase chain reaction validation. In addition, the experimental framework incorporated direct serum complement profiling, single-cell transcriptomic sequencing, flow cytometry, and a structured six-month clinical outcome assessment to monitor host biological changes throughout disease management.

Across the integrated peripheral blood mononuclear cell transcriptomic datasets, an analysis of gene expression patterns identified a prominent classical complement module centered on C1q that responded directly to clinical status and intervention. Genes associated with C1q exhibited significant upregulation in patients with active tuberculosis relative to non-active states, followed by a measurable decrease after patients received standard anti-tuberculosis treatment. Furthermore, this C1q-centered gene network demonstrated greater enrichment in patients diagnosed with severe tuberculosis disease. When investigators performed clinical validation in peripheral blood mononuclear cells using quantitative real-time PCR, they confirmed marked increases in C1r, C1QB, and complement receptor 2 (CR2) expression in active tuberculosis, along with significant transcriptional enrichment of C1r, C1QB, and C1QC among severe cases.

Complement alterations were also observed directly in circulating blood through comprehensive serum-level profiling, reflecting active cascade stimulation and dysregulated receptor pathways. Serum assessments revealed elevated concentrations of circulating C1q alongside increased levels of the soluble membrane attack complex, commonly designated as sMAC. Concurrently, the researchers measured a reduction in soluble complement receptor 2, or sCR2, in patient serum samples. These combined protein measurements were consistent with systemic complement activation paired with altered complement receptor-related regulation. Additionally, circulating levels of the regulatory molecule CD46 were found to be increased specifically in individuals experiencing severe tuberculosis, underscoring pronounced pathway modulation in more advanced disease presentations.

The peripheral complement-related parameters measured across the cohort closely tracked systemic inflammatory and clinical indices, providing quantitative markers of patient disease state. Crucially, the researchers identified significant associations between these complement measurements and clinical outcomes assessed at six months of follow-up. This longitudinal evaluation provided further empirical evidence linking the observed complement response to ongoing tuberculosis disease progression.

To identify which leukocyte subsets mediate these complement alterations, the authors carried out single-cell transcriptomics and flow cytometry on patient blood samples. These cellular analyses localized the complement-associated signals predominantly to circulating monocyte populations situated within a broader myeloid-skewed systemic inflammatory landscape. Taken together, the study findings suggest that peripheral complement remodeling represents an inflammatory host-response feature linked to monocytes that correlates directly with tuberculosis progression, activity, and severity. The authors noted that this observational biomarker investigation did not constitute an interventional clinical trial.

Subject of Research: Peripheral complement remodeling as a marker of tuberculosis activity and disease progression

Article Title: From pathogen burden to host response: complement remodeling as a marker of TB activity

Article References: Gong, Z., Yan, J., Shi, Y., Zhou, Q., Chu, W., Ye, N., & Wang, G. (2026). From pathogen burden to host response: complement remodeling as a marker of TB activity. BMC Microbiology. https://doi.org/10.1186/s12866-026-05860-5

Image Credits: AI Generated

DOI: 10.1186/s12866-026-05860-5

Keywords: tuberculosis, complement system, host inflammatory response, C1q, C1r, C1QB, C1QC, CR2, soluble membrane attack complex, sCR2, CD46, monocytes, PBMC transcriptomics, flow cytometry, single-cell transcriptomics, anti-TB treatment, disease severity, clinical outcomes