Abstract
Innate immunity in animals including humans encompasses the complement system, which is considered an important host defense mechanism against Aspergillus fumigatus, one of the most ubiquitous opportunistic human fungal pathogens. Previously, it has been shown that the alkaline protease Alp1p secreted from A. fumigatus mycelia degrades the complement components C3, C4, and C5. However, it remains unclear how the fungal spores (i.e. conidia) defend themselves against the activities of the complement system immediately after inhalation into the lung. Here, we show that A. fumigatus conidia contain a metalloprotease Mep1p, which is released upon conidial contact with collagen and inactivates all three complement pathways. In particular, Mep1p efficiently inactivated the major complement components C3, C4, and C5 and their activation products (C3a, C4a, and C5a) as well as the pattern-recognition molecules MBL and ficolin-1, either by directly cleaving them or by cleaving them to a form that is further broken down by other proteases of the complement system. Moreover, incubation of Mep1p with human serum significantly inhibited the complement hemolytic activity and conidial opsonization by C3b and their subsequent phagocytosis by macrophages. Together, these results indicate that Mep1p associated with and released from A. fumigatus conidia likely facilitates early immune evasion by disarming the complement defense in the human host.
Highlights
Innate immunity in animals including humans encompasses the complement system, which is considered an important host defense mechanism against Aspergillus fumigatus, one of the most ubiquitous opportunistic human fungal pathogens
The diverse strategies employed by the complement system for elimination of pathogens are as follows: (i) formation of a membrane attack complex (MAC)5 on the microbial membrane resulting in their lysis; (ii) promotion of microbial phagocytosis by opsonization and their uptake through complement receptors; (iii) recruitment of immune cells by anaphylatoxins; and (iv) enhancement of T and B cell responses [2,3,4,5,6]
Human bronchoalveolar lavage is reported to contain complement proteins [35], which prompted us to examine whether A. fumigatus conidia store protease(s) capable of subverting the complement system in the lungs
Summary
The A. fumigatus morphotype that enters the human lungs and first exposed to the alveolar environment is mainly A. fumigatus conidia. The CS showed limited cleavage of C3b but efficiently cleaved C4b; the proteolytic activity was directed against the ␣Ј-chain of C4b (Fig. 1, A and B). This indicated that a protease (or proteases) stored in the conidia, and released early on, is responsible for cleaving C4b. There was a band corresponding to Mep1p on Western blotting upon probing SDS-PAGE–separated BALF using polyclonal anti-Mep1p antibody, suggesting that Mep1p is released into the lung environment. These results were confirmed by ELISA (Fig. 1F). Mep1p efficiently cleaved properdin (FP), MBL, ficolin-1, and C4BP and showed limited activity toward ficolin-2, -3, IgG, and FH suggesting Mep1p targets multiple complement components (Fig. 4)
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