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

Tuberculosis (TB) progression is shaped by host inflammatory remodeling, not only by pathogen burden. Here, we investigated whether peripheral complement dysregulation represents a host-response program associated with tuberculosis disease activity, disease severity, and clinical outcomes. We integrated public peripheral blood mononuclear cell (PBMC) transcriptomic data, clinical qRT-PCR validation, serum complement profiling, single-cell transcriptomics, flow cytometry, and 6-month outcome assessment. A treatment-responsive C1q-centered classical complement module emerged across datasets: C1q-related genes were increased in active TB, decreased after anti-TB treatment, and were further enriched in severe disease. Clinical PBMC analyses confirmed increased C1r, C1QB, and CR2 in active TB and enrichment of C1r, C1QB, and C1QC in severe TB. At the serum level, increased C1q and soluble membrane attack complex (sMAC), together with reduced soluble complement receptor 2 (sCR2), were consistent with complement activation and altered complement receptor-related regulation; CD46 was also increased in severe disease. Complement-related measures tracked systemic inflammatory and clinical indices, while associations with 6-month outcome provided additional evidence linking this response to disease progression. Single-cell and flow cytometry analyses localized complement-associated signals mainly to monocyte populations within a myeloid-skewed inflammatory landscape. Collectively, these findings suggest that peripheral complement remodeling represents a monocyte-linked inflammatory host-response feature associated with tuberculosis progression. Clinical trial number: Not Applicable.