Mannose-binding lectin (MBL) is the main complement activator on Aspergillus fumigatus conidia under immunocompromised conditions

Abstract

Abstract Aspergillus fumigatus is normally a non-pathogenic fungus, but in immunocompromised patients this fungus becomes highly pathogenic. Complement activation are thought to be of crucial importance for elimination of A. fumigatus. However, which of the three complement pathways that are important under immunocompromised conditions are only partly understood. Conidia from a clinical isolate of A. fumigatus were co-incubated with serum before complement activation products C4b, C3b and TCC were measured in flow cytometry. Besides normal (NHS) and complement deficient sera plus complement inhibitors, we used umbilical cord serum (UCS) to mimic a compromised immune defense reflected in the low immunoglobulin (Ig) levels. In NHS, the classical pathway was the dominant initiator with the alternative pathway providing a strong C3b amplification. Classical pathway is known to be initiated via C1q binding to Ig, whereas MBL and ficolin-2 from the lectin pathway bind the fungus directly. UCS conveyed low IgG and no IgM binding to the conidia, and we observed that complement activation on A. fumigatus in UCS was predominantly MBL dependent. UCS with low MBL had significantly lower C3b deposition than serum from NHS with low MBL. Moreover, a close positive correlation between MBL levels and C3b deposition in UCS (Spearman r = 0.79, p < 0.0001, n = 23) was observed. The significance of MBL was emphasized by decreased neutrophilic phagocytosis of conidia via MBL inhibition in C1q−/− serum. We conclude that MBL is the main complement activator and phagocytosis initiator of A. fumigatus conidia in individuals with low Ig levels. This suggests a crucial role for the lectin pathway in protection against infection of A. fumigatus in immunocompromised patients.