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The complement system labels microbes and host debris for clearance. Degradation of surface-bound C3b is pivotal to direct immune responses and protect host cells. How the serine protease factor I (FI), assisted by regulators, cleaves either two or three distant peptide bonds in the CUB domain of C3b remains unclear. We present a crystal structure of C3b in complex with FI and regulator factor H (FH; domains 1-4 with 19-20). FI binds C3b-FH between FH domains 2 and 3 and a reoriented C3b C-terminal domain and docks onto the first scissile bond, while stabilizing its catalytic domain for proteolytic activity. One cleavage in C3b does not affect its overall structure, whereas two cleavages unfold CUB and dislodge the thioester-containing domain (TED), affecting binding of regulators and thereby determining the number of cleavages. These data explain how FI generates late-stage opsonins iC3b or C3dg in a context-dependent manner, to react to foreign, danger or healthy self signals.

Background: The diagnosis of neonatal sepsis remains a challenge as the condition lacks early clinical signs and reliable biomarkers. Objectives: The aim of our study was to determine whether serum mannose binding lectin (MBL) levels and genotypes of MBL2 gene could be used as markers for predicting neonatal sepsis in the Chinese Han population. Methods: This prospective study was hospital-based in design. 48 neonates with clinical signs and symptoms of septicemia (study group), and 96 infants with no infection (control) were included. All the neonates are Chinese Han descent. MBL2 promoter polymorphisms at positions -550, -221 and +4 were analyzed by direct sequencing, and serum MBL levels were estimated by enzyme-linked immunesorbent assay. Results: Frequencies of genotype -221 YX were significantly higher in the study group (45.8%) compared with the control group (15.60%; P = 0.00009). The median serum MBL level was found to be significantly lower in infants who had the -221YX genotype (214.54 ng/mL) compared with those who had the -221YY genotype (597.85 ng/mL; P < 0.0001). Additionally, the median of serum MBL was significantly lower in infants with septicemia (289.65 ng/mL) than in controls (597.75 ng/mL; P = 0.041). According to ROC analysis, the cutoff value of MBL concentration ≤ 384.60 (ng/mL) had a sensitivity of 0.806 and a specificity of 0.777 for predicting sepsis. Conclusions: This study suggested that serum MBL and the -221 YX genotype of the MBL2 gene might be predisposed factors for sepsis in the Chinese Han population.

Regulators of complement activation (RCA) inhibit complement‐induced immune responses on healthy host tissues. We present crystal structures of human RCA (MCP, DAF, and CR1) and a smallpox virus homolog (SPICE) bound to complement component C3b. Our structural data reveal that up to four consecutive homologous CCP domains (i–iv), responsible for inhibition, bind in the same orientation and extended arrangement at a shared binding platform on C3b. Large sequence variations in CCP domains explain the diverse C3b‐binding patterns, with limited or no contribution of some individual domains, while all regulators show extensive contacts with C3b for the domains at the third site. A variation of ~100° rotation around the longitudinal axis is observed for domains binding at the fourth site on C3b, without affecting the overall binding mode. The data suggest a common evolutionary origin for both inhibitory mechanisms, called decay acceleration and cofactor activity, with variable C3b binding through domains at sites ii, iii, and iv, and provide a framework for understanding RCA disease‐related mutations and immune evasion.