Bifunctional Small Molecules Enhance Neutrophil Activities Against Aspergillus fumigatus in vivo and in vitro

We report that the bifunctional compounds enhance the interactions between primary human neutrophils and A. fumigatus in vitro, using three microfluidic assay platforms. The bifunctional compounds significantly enhance the recruitment of neutrophils, increase hyphae killing by neutrophils in a uniform concentration of drug, and decrease hyphal tip growth velocity in the presence of neutrophils compared to the antifungal targeting moiety alone. We validated that the bifunctional compounds are also effective in vivo, using a zebrafish infection model with neutrophils expressing the appropriate EM receptor. We measured significantly increased phagocytosis of A. fumigatus conidia by neutrophils expressing the EM receptor in the presence of the compounds compared to receptor-negative cells. Finally, we demonstrate that treatment with our lead compound significantly improved the antifungal activity of neutrophils from immunosuppressed patients ex vivo. This type of bifunctional compounds strategy may be utilized to redirect the immune system to destroy fungal, bacterial, and viral pathogens. Introduction Humans are continuously exposed to airborne spores of the saprophytic fungus Aspergillus fumigatus (A. fumigatus). In healthy individuals, pulmonary host defense mechanisms efficiently eliminate this mold. However, the incidence of invasive pulmonary aspergillosis (IPA) has risen in recent decades, reflecting the increasing number of immunosuppressive medical interventions su...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research