Fungal Mimicry of a Mammalian Aminopeptidase Disables Innate Immunity and Promotes Pathogenicity

Abstract

Systemic fungal infections trigger marked immune-regulatory disturbances, but the mechanisms are poorly understood. We report that the pathogenic yeast of Blastomyces dermatitidis elaborate dipeptidylpeptidase IVA (DppIVA), a close mimic of the mammalian ectopeptidase CD26, which modulates critical aspects of hematopoiesis. We show that, like the mammalian enzyme, fungal DppIVA cleaved C-C chemokines and GM-CSF. Yeast producing DppIVA crippled the recruitment and differentiation of monocytes, and prevented phagocyte activation and ROS production. Silencing fungal DppIVA gene expression curtailed virulence and restored recruitment of CCR2+ monocytes, generation of TipDC, and phagocyte killing of yeast. Pharmacological blockade of DppIVA restored leukocyte effector functions and stemmed infection, while addition of recombinant DppIVA to gene-silenced yeast enabled them to evade leukocyte defense. Thus, fungal DppIVA mediates immune-regulatory disturbances that underlie invasive fungal disease. These findings reveal of form of molecular piracy by a broadly conserved aminopeptidase during disease pathogenesis.

Immunity against fungi

“…Murine Ly6C hi monocytes represent effector cells against C. albicans (99), A. fumigatus (100), and B. dermatiditis (101). During repetitive challenges with β-glucans, murine Ly6C hi monocytes and human CD14 + monocytes exhibit attributes reminiscent of immunologic memory, including enhanced responsiveness, based on cytokine responses (102).…”

Human iNKT Cells Promote Protective Inflammation by Inducing Oscillating Purinergic Signaling in Monocyte-Derived DCs

“…Neutrophils were enriched from bone marrow of C57Bl/6 mice using Percoll density-gradient centrifugation as previously described (Sterkel et al, 2016). Neutrophils and C. albicans yeast were suspended at ratios of 1:1 or 1:2 in assay culture medium (RPMI 1640, 2% FBS, and 100 μg/ml penicillin and streptomycin) containing 1/4- to 1/8-fold dilutions of filtered supernatants from cultures of iNKT cells alone, DCs alone, or iNKT cells and DCs or of T cell medium lacking cells as a negative control.…”

Anti-Immune Strategies of Pathogenic Fungi

“…However, Blastomyces dermatitidis have the ability to interfere with Ly 6 C hi recruitment after respiratory vaccination by inducing MMP2 (lung matrix metalloproteinase 2), which suppresses CCL7, one of the signals for monocyte recruitment (Wüthrich et al, 2012). In addition, B. dermatitidis DppIVA, which is a multifunctional protein that can act as a serine protease, assists in evasion of the host immune response during infection by cleaving CCL7, a C-C chemokine signal, which recruits Ly6Chi CCR2+ monocytes to the sites of infection (Sterkel et al, 2016). DppIVA also acts on mammalian GM-CSF (granulocyte-macrophage colony-stimulating factor), which is involved in the differentiation and activation of monocytes, macrophages, dendritic cells, and neutrophils during the immune response to pathogens.…”

“…DppIVA also acts on mammalian GM-CSF (granulocyte-macrophage colony-stimulating factor), which is involved in the differentiation and activation of monocytes, macrophages, dendritic cells, and neutrophils during the immune response to pathogens. Inactivation of GM-CSF indirectly affects the production of ROS, increasing the survival of fungi (Sterkel et al, 2016). …”