β-1,3-glucan-lacking<i>Aspergillus fumigatus</i>mediates an efficient antifungal immune response by activating complement and dendritic cells

Abstract

Complement system and dendritic cells (DCs) form - beside neutrophils and macrophages - the first line of defense to combat fungal infections. Therefore, we here studied interactions of these first immune elements with <i>Aspergillus fumigatus</i> lacking ß-1,3-glucans (<i>fks1_tetOn^rep</i> under repressed conditions) to mechanistically explain the mode of action of echinocandins in more detail. Echinocandins are cell wall active agents blocking β-glucan synthase, making the <i>A. fumigatus fks1_tetOn</i> mutant a good model to study immune-modulatory actions of these drugs. We now demonstrate herein, that complement was activated to significantly higher levels by the <i>fks1-</i>deficient strain compared to its respective wild type. This enhanced covalent linking of complement fragments to the <i>A. fumigatus fks1_tetOn^rep</i> mutant further resulted in enhanced DC binding and internalization of the fungus. Additionally, we found that <i>fks1_tetOn^rep</i> induced a Th1-/Th17-polarizing cytokine profile program in DCs. The effect was essentially dependent on massive galactomannan shedding, since blocking of DC-SIGN significantly reduced the <i>fks1_tetOn^rep-</i>mediated induction of an inflammatory cytokine profile.Our data demonstrate that lack of ß-1,3-glucan, also found under echinocandin therapy, results in improved recognition of <i>Aspergillus fumigatus</i> by complement and DCs and therefore not only directly affects the fungus by its fungistatic actions, but also is likely to exert indirect antifungal mechanisms by strengthening innate host immune mechanisms.<b>Abbreviations</b>: C: complement; CR:complement receptor; DC: dendritic cell; iDC: immature dendritic cell; DC-SIGN: Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin; ERK: extracellular signal-regulated kinases; JNK : c-Jun N-terminal kinases; MAPK: mitogen-activated protein kinase; NHS: normal human serum; PRR: pattern recognition receptor; Th :T helper; TLR :Toll-like receptor; WT: wild type.