Aspf2 From Aspergillus fumigatus Recruits Human Immune Regulators for Immune Evasion and Cell Damage

Abstract

The opportunistic fungal pathogen Aspergillus fumigatus can cause life-threatening infections, particularly in immunocompromised patients. Most pathogenic microbes control host innate immune responses at the earliest time, already before infiltrating host immune cells arrive at the site of infection. Here, we identify Aspf2 as the first A. fumigatus Factor H-binding protein. Aspf2 recruits several human plasma regulators, Factor H, factor-H-like protein 1 (FHL-1), FHR1, and plasminogen. Factor H contacts Aspf2 via two regions located in SCRs6–7 and SCR20. FHL-1 binds via SCRs6–7, and FHR1 via SCRs3–5. Factor H and FHL-1 attached to Aspf2-maintained cofactor activity and assisted in C3b inactivation. A Δaspf2 knockout strain was generated which bound Factor H with 28% and FHL-1 with 42% lower intensity. In agreement with less immune regulator acquisition, when challenged with complement-active normal human serum, Δaspf2 conidia had substantially more C3b (>57%) deposited on their surface. Consequently, Δaspf2 conidia were more efficiently phagocytosed (>20%) and killed (44%) by human neutrophils as wild-type conidia. Furthermore, Aspf2 recruited human plasminogen and, when activated by tissue-type plasminogen activator, newly generated plasmin cleaved the chromogenic substrate S2251 and degraded fibrinogen. Furthermore, plasmin attached to conidia damaged human lung epithelial cells, induced cell retraction, and caused matrix exposure. Thus, Aspf2 is a central immune evasion protein and plasminogen ligand of A. fumigatus. By blocking host innate immune attack and by disrupting human lung epithelial cell layers, Aspf2 assists in early steps of fungal infection and likely allows tissue penetration.

EphA2-Dependent Internalization of A. fumigatus Conidia in A549 Lung Cells Is Modulated by DHN-Melanin

“…The binding to plasminogen leads to increased damage of A549 cells after adhesion of the conidia. Deletion of Aspf2 leads to a decrease in A549 cell damage, but also to a decrease in internalization in macrophages ( Dasari et al, 2018 ).…”

Proteome analysis of bronchoalveolar lavage fluids reveals host and fungal proteins highly expressed during invasive pulmonary aspergillosis in mice and humans

“…There are several reports of the detection of AspF2 in ABPA and AspF2 is recognized by specific IgE antibodies in these patients [60,61]. AspF2 was recently shown to recruit several plasma regulators, Factor H, Factor H-like protein, and plasminogen, thereby blocking host immune attack [62]. AspF2 was previously shown to be induced at low zinc levels [63].…”

Biotinylated Surfome Profiling Identifies Potential Biomarkers for Diagnosis and Therapy of Aspergillus fumigatus Infection

“…Proteins on the surface mediate direct contacts between pathogens and hosts. In addition to several known surface proteins, such as RodA, CalA, Asp f 2, and CcpA (10,12,16,19), abundant surface proteins detected in this study, such as Tef1, ArtA, Hsp70, and Hsp90, also have the potential to interact with a range of host proteins (44). Candida albicans Tef1 was shown to be surface localized and to be able to bind human Table 5), including the results obtained in this study (CEA10 B, corresponding to all the morphotypes of CEA10 obtained using the biotinylation method); the surfome of CEA10 (CEA10 T, corresponding to all the morphotypes of CEA10 obtained using the trypsin-shaving method); D141 (dormant and swollen conidia) results obtained using the trypsin shaving method (10,11); the CEA17ΔakuB KU80 dormant conidia surfome results obtained using the formic acid extract (9); and the ATCC 46645 surfome detected by hydrogen fluoride-pyridine extraction and trypsin shaving (10).…”