Abstract
Aspergillosis cases by Aspergillus fumigatus have increased, along with fungal resistance to antifungals, urging the development of new therapies. Passive immunization targeting common fungal antigens, such as chitin and β-glucans, are promising and would eliminate the need of species-level diagnosis, thereby expediting the therapeutic intervention. However, these polysaccharides are poorly immunogenic. To overcome this drawback, we developed the lectin-Fc(IgG) fusion proteins, Dectin1-Fc(IgG2a), Dectin1-Fc(IgG2b) and wheat germ agglutinin (WGA)-Fc(IgG2a), based on their affinity to β-1,3-glucan and chitooligomers, respectively. The WGA-Fc(IgG2a) previously demonstrated antifungal activity against Histoplasma capsulatum, Cryptococcus neoformans and Candida albicans. In the present work, we evaluated the antifungal properties of these lectin-Fc(s) against A. fumigatus. Lectin-Fc(IgG)(s) bound in a dose-dependent manner to germinating conidia and this binding increased upon conidia germination. Both lectin-Fc(IgG)(s) displayed in vitro antifungal effects, such as inhibition of conidia germination, a reduced length of germ tubes and a diminished biofilm formation. Lectin-Fc(IgG)(s) also enhanced complement deposition on conidia and macrophage effector functions, such as increased phagocytosis and killing of fungi. Finally, administration of the Dectin-1-Fc(IgG2b) and WGA-Fc(IgG2a) protected mice infected with A. fumigatus, with a 20% survival and a doubled life-span of the infected mice, which was correlated to a fungal burden reduction in lungs and brains of treated animals. These results confirm the potential of lectin-Fc(IgGs)(s) as a broad-spectrum antifungal therapeutic.
Highlights
Invasive fungal infections, such as aspergillosis caused by Aspergillus fumigatus, are a growing public health problem with high levels of morbidity and mortality in many countries [1]
In this work, taking advantage/benefitting of the existing of wheat germ agglutinin (WGA)-Fc(IgG2a) with potential antifungal functions and two comparable Fc-fusion proteins produced in our laboratory, Dectin-1-Fc(IgG2a) and Dectin-1-Fc(IgG2b), we demonstrate that they efficiently recognized A. fumigatus germinating conidia, and were able to increase complement activation, phagocytosis by macrophages and their antifungal functions
A. fumigatus NCPF 2109 (ATCC® 46645 TM) strain was grown on Potato Dextrose Agar (PDA; Neogen, Lansing, MI, USA) supplemented with 5% penicillin-streptomycin (Gibco® -Life Technologies) and isolation of conidia was performed as described, with some slight modifications [45,46,47]
Summary
Invasive fungal infections, such as aspergillosis caused by Aspergillus fumigatus, are a growing public health problem with high levels of morbidity and mortality in many countries [1]. A. fumigatus and A. flavus are the Aspergillus species with medical importance causing death in immunocompromised patients [10]. Aspergillosis is generally difficult to diagnose, with an often complicated and ineffective treatment, resulting in a high mortality rate (10–40%) [14]. Triazoles such as itraconazole, voriconazole, and posaconazole are the main oral therapy for A. fumigatus infections [15].
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