The Opportunistic Human Pathogenic FungusAspergillus fumigatusEvades the Host Complement System

Abstract

The opportunistic human pathogenic fungus Aspergillus fumigatus causes severe systemic infections and is a major cause of fungal infections in immunocompromised patients. A. fumigatus conidia activate the alternative pathway of the complement system. In order to assess the mechanisms by which A. fumigatus evades the activated complement system, we analyzed the binding of host complement regulators to A. fumigatus. The binding of factor H and factor H-like protein 1 (FHL-1) from human sera to A. fumigatus conidia was shown by adsorption assays and immunostaining. In addition, factor H-related protein 1 (FHR-1) bound to conidia. Adsorption assays with recombinant factor H mutants were used to localize the binding domains. One binding region was identified within N-terminal short consensus repeats (SCRs) 1 to 7 and a second one within C-terminal SCR 20. Plasminogen was identified as the fourth host regulatory molecule that binds to A. fumigatus conidia. In contrast to conidia, other developmental stages of A. fumigatus, like swollen conidia or hyphae, did not bind to factor H, FHR-1, FHL-1, and plasminogen, thus indicating the developmentally regulated expression of A. fumigatus surface ligands. Both factor H and plasminogen maintained regulating activity when they were bound to the conidial surface. Bound factor H acted as a cofactor to the factor I-mediated cleavage of C3b. Plasminogen showed proteolytic activity when activated to plasmin by urokinasetype plasminogen activator. These data show that A. fumigatus conidia bind to complement regulators, and these bound host regulators may contribute to evasion of a host complement attack.

Innate Immunity toAspergillusSpecies

“…This improved outcome was associated with enhanced production of TNF and gamma interferon (IFN-␥) and reduced production of IL-10 by cultured splenocytes of infected animals (78). On the other hand, resting Aspergillus species are capable of binding several complement regulatory proteins including factor H and plasminogen, thereby inhibiting the activation of the complement cascade (13). In this context, a mutated form of the plasminogen gene was associated with susceptibility to invasive aspergillosis in immunocompromised mice and a similar single-nucleotide polymorphism in human plasminogen predisposes hematopoietic stem cell recipients to invasive aspergillosis (174).…”

Factor H and Factor H-Related Protein 1 Bind to Human Neutrophils via Complement Receptor 3, Mediate Attachment to Candida albicans, and Enhance Neutrophil Antimicrobial Activity

“…The opportunistic human pathogenic fungi Candida albicans and Aspergillus fumigatus interact with the host complement system and bind the regulators CFH, CFHL1, and C4b-binding protein (6,14,(17)(18)(19). These regulators may limit complement activation on the fungal surface and reduce the amount of pathogenbound opsonins, thus influencing opsonophagocytosis.…”

“…Unlike CFH, CFHR1 seems to regulate the terminal pathway of complement (10). CFHR1 binds to several microbes (11)(12)(13)(14)(15)(16), and because of its ability to compete with CFH for binding sites, CFHR1 may reduce complement inhibition at the pathogen surface (13).…”

SecretedAspergillus fumigatusProtease Alp1 Degrades Human Complement Proteins C3, C4, and C5

“…The complement activation system is controlled by fluid-phase and cell surface-bound regulators. We and others showed before (2,62) that A. fumigatus conidia bind factor H (the central human regulator of the AP), FHL-1, and CFHR1. Factor H acts as a cofactor for the plasma serine protease factor I, which mediates the cleavage of C3b (21,35,41).…”