Aspergillus fumigatus conidial metalloprotease Mep1p cleaves host complement proteins

Abstract

Innate immunity in animals including humans encompasses the complement system, which is considered an important host defense mechanism against , one of the most ubiquitous opportunistic human fungal pathogens. Previously, it has been shown that the alkaline protease Alp1p secreted from mycelia degrades the complement components C3, C4, and C5. However, it remains unclear how the fungal spores ( conidia) defend themselves against the activities of the complement system immediately after inhalation into the lung. Here, we show that 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 conidia likely facilitates early immune evasion by disarming the complement defense in the human host.

Peptidylarginine Deiminase of Porphyromonas gingivalis Modulates the Interactions between Candida albicans Biofilm and Human Plasminogen and High-Molecular-Mass Kininogen

“…Pathogenic microorganisms use various mechanisms to increase their virulence potential and successfully invade a host organism whilst avoiding the host immune response. This includes the modulation of important host plasma homeostatic systems such as the coagulation and fibrinolysis systems, the complement system, and the kinin generation system (also known as the contact system) [45,46,[49][50][51][52]. One of the mechanisms that facilitates the interference by pathogens of plasma homeostatic systems is the binding of their individual components to the surfaces of microbial cells, which contributes to the local increase in their concentration and further processing by proteases, or to the insidious takeover of these components and their exclusion from the host systems [53,54].…”

The complement system in Aspergillus fumigatus infections and its crosstalk with pentraxins

“…A mechanism has been proposed here that involves either direct degradation of these proteins or their cleavage to forms that are further processed (and inactivated) in solution by complement proteases. However, an Mep1p-deficient A. fumigatus mutant showed similar virulence to that of the WT strain in a immunosuppressed murine model of IPA, suggesting a certain degree of redundancy amongst the proteolytic mechanisms evolved by this fungus [96].…”

“…The complement-dependent disposal of the fungal pathogen is mostly mediated by opsonic and phagocytic mechanisms, with direct membrane lysis (i.e., by MAC formation) playing a minor role, due to thickness and resistance of the cell wall [23]. A. fumigatus has evolved several strategies to evade the complement response, including secretion of proteases (i.e., Alp1 [94] and Mep1p [96]) that targets key components of the system, such as C3 and C1q (as well as C4 and C5, not shown in the figure), and recruitment of inhibitors of the AP (i.e., factor H, fH) [89] and CP/LP (i.e., C4BP) [90]. contributed to complement activation in conditions of C1q deficiency and MBL competence [52].…”

“…In this respect, the hyphal morphotype was found to secrete the Alp1 protease that degrades C3, C4, and C5, and has been proposed to exert an important role in cerebral aspergillosis [94,95]. More recently, an A. fumigatus metalloprotease has been described (i.e., Mep1p) that is synthesized by the dormant conidia in the presence of collagen (to model the lung ECM), and acts on the same subset of complement components, in addition to their anaphylatoxin products (i.e., C3a, C4a, and C5a) and the LP initiators MBL and ficolin-1 [96]. A mechanism has been proposed here that involves either direct degradation of these proteins or their cleavage to forms that are further processed (and inactivated) in solution by complement proteases.…”

Genetic underpinnings of host manipulation byOphiocordycepsas revealed by comparative transcriptomics

“…Genes with MEROPS M43.002 putatively function similarly to mep1, which assists fungi to counteract mammalian immune systems (HUNG & al. 2005, SHENDE & al. 2018.…”