The Role of Serum Ficolins in the Innate Immune Response to Aspergillus species.

Abstract Aspergillus fumigatus is an opportunistic fungal pathogen that is capable of causing the devastating disease invasive aspergillosis (IA) in immunocompromised patients following the inhalation of airborne conidia. IA is associated with a mortality rate of up to 90% and is notoriously difficult to diagnose. We were therefore interested whether recently described pathogen recognition molecules, termed ficolins, could contribute to innate resistance against A. fumigatus and whether they could be used as novel biomarkers for fungal infection. Serum ficolins from both humans (L- and H-ficolin) and rodents (ficolin-A) bound to A. fumigatus in a concentration-, calcium- and pH-dependent manner and binding was abolished by competition with defined carbohydrates. This ficolin opsonisation could augment the association of A. fumigatus conidia with A549 type II pneumocytes, monocyte-derived macrophages (MDM) and neutrophils. Additionally, ficolin opsonisation led to potentiation of the fungal killing response by MDM and neutrophils, but not by A549 cells. H-ficolin was observed to participate in lectin complement pathway activation on A. fumigatus but ficolin-A was not involved in complement activation. Challenging A549 cells with ficolin opsonised A. fiumigatus induced a significant increase in IL-8 production and this increase was abrogated by inhibition of MEK 1/2, p38 MAPK and JNK. Conversely, we indicated that ficolin opsonisation significantly downregulated IL-1β, IL-6, IL-8, IL-10 and TNF-α production by MDM and neutrophils, highlighting a novel anti-inflammatory function. Interestingly, we provided the first observation that L-ficolin could be found in the lung and was predominantly present during fungal infection. In addition, H-ficolin was also found in greater concentrations within infected lungs. These observations demonstrated that the recognition of A. fumigatus by serum ficolins was important in induction of cell-mediated innate immune responses to A. fumigatus challenge. Moreover, the observations highlighted the potential of H- and L-ficolin as novel biomarkers in the diagnosis of fungal lung infections.

Name dc:type.qualificationname

phd

Level dc:type.qualificationlevel

doctoral

Grantor dc:publisher.institution

University of East Anglia

Year dc:date.issued

2016

Author dc:creator

• Bidula, Stefan

Language dc:language

en