Histidine-Rich Glycoprotein Protects from Systemic Candida Infection

Abstract

Fungi, such as Candida spp., are commonly found on the skin and at mucosal surfaces. Yet, they rarely cause invasive infections in immunocompetent individuals, an observation reflecting the ability of our innate immune system to control potentially invasive microbes found at biological boundaries. Antimicrobial proteins and peptides are becoming increasingly recognized as important effectors of innate immunity. This is illustrated further by the present investigation, demonstrating a novel antifungal role of histidine-rich glycoprotein (HRG), an abundant and multimodular plasma protein. HRG bound to Candida cells, and induced breaks in the cell walls of the organisms. Correspondingly, HRG preferentially lysed ergosterol-containing liposomes but not cholesterol-containing ones, indicating a specificity for fungal versus other types of eukaryotic membranes. Both antifungal and membrane-rupturing activities of HRG were enhanced at low pH, and mapped to the histidine-rich region of the protein. Ex vivo, HRG-containing plasma as well as fibrin clots exerted antifungal effects. In vivo, Hrg−/− mice were susceptible to infection by C. albicans, in contrast to wild-type mice, which were highly resistant to infection. The results demonstrate a key and previously unknown antifungal role of HRG in innate immunity.

C-terminal Peptides of Tissue Factor Pathway Inhibitor Are Novel Host Defense Molecules

“…The presently disclosed direct antibacterial action of C-terminal peptides of TFPI is in line with observations indicating that heparin-binding proteins, such as complement C3 (25), kininogen (36,37), heparin-binding protein (38), heparin-binding epidermal growth factor and other growth factors (39), heparin/heparan sulfate-interacting protein (40), ␤2-glycoprotein (41), histidine-rich glycoprotein (42), and human thrombin (43) may, either as holoproteins or after fragmentation, exert antimicrobial activities in vitro and, in several cases, in vivo (36,37,42). In addition, peptide-mediated C3a generation, along with enhanced MAC formation, represents a mechanism by which a host defense peptide may selectively enhance microbial killing by generation of additional complement-derived AMPs.…”

Histidine-rich glycoprotein is a novel plasma pattern recognition molecule that recruits IgG to facilitate necrotic cell clearance via FcγRI on phagocytes

“…12 Furthermore, because the binding of ␤ 2 GPI to apoptotic cells via anionic phospholipids has been proposed to initiate the break of tolerance and induce the generation of anti-␤ 2 GPI or antiphospholipid-␤ 2 GPI complex autoantibodies, 46 the interaction between HRG and phospholipids in necrotic cells may provide a potential mechanism for generating anti-HRG autoantibodies, as suggested by Ball-Rosen et al 29 In addition to regulating coagulation and fibrinolysis, HRG has also been shown to bind to and facilitate the removal of bacteria 47,48 and fungi. 49 The specific binding of HRG to pathogens [47][48][49] and molecular structures exposed on necrotic cells, as shown in this study, clearly highlights its ability to function as a PRM like C1q, CRP, MBL, and ␤ 2 GPI. Interestingly, these PRMs, including HRG, are frequently targeted by autoantibodies.…”

Proteolytic Activation Transforms Heparin Cofactor II into a Host Defense Molecule

“…Further, in contrast to the helical and antimicrobial LL-37 (31) and C-terminal thrombin peptides (12), found to be released from their holoproteins hCAP18 and thrombin, respectively, the herein described HCIIa form per se mediates the bactericidal and LPS-binding effects. In this perspective, the molecule therefore belongs to the class of larger antimicrobial proteins such as antimicrobial RNases (32), eosinophil cationic protein (33), lactoferrin (34), PCI (29), and histidine-rich glycoprotein (35), which all exert bactericidal effects, albeit without the need for the critical and unique enzymatic activation, followed by the dramatic shift in net charge, and the shape transition observed for HCII in this work.…”