Reduced expression of TLR3, TLR10 and TREM1 by human macrophages in Chronic cavitary pulmonary aspergillosis, and novel associations of VEGFA, DENND1B and PLAT.
Chronic cavitary pulmonary aspergillosis (CCPA) is an uncommon but serious pulmonary disease of humans, with an annual mortality rate of 10-30%. It is caused by the fungus Aspergillus fumigatus. Patients are overtly immunocompetent; however, some immunogenetic defect is likely. To investigate this, we performed a genetic association study analysing biologically plausible candidate genes in 112 CCPA patients and 279 healthy controls, and investigated gene expression in monocyte-derived macrophages from patients and controls at baseline and during stimulation with A. fumigatus. Single-nucleotide polymorphisms (SNPs) associated with CCPA were found in TLR1, CLEC7A (dectin-1), PLAT (n=2), VEGFA, and DENND1B. Macrophages from CCPA patients showed low TLR3 and TLR10 expression and high TREM1 expression at baseline, as compared with macrophages from healthy subjects, with major expression differences being seen in most Toll-like receptors (TLRs) during 9 h of co-culture with A. fumigatus. The differences in baseline expression between the healthy and CCPA groups suggest roles for TLR3 and TLR10 in susceptibility to CCPA, and the association of SNPs in PLAT (n=2), VEGFA and DENND1B supports novel roles for plasminogen activation and angiogenesis and of these genes specifically in susceptibility to CCPA.
Manchester Fungal Infection Group (MFIG), University of Manchester, Manchester, UK; Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK; Manchester Academic Health Science Centre, Manchester, UK; University Hospital South Manchester NHS Foundation Trust, Manchester, UK; NIHR South Manchester Respiratory and Allergy Clinical Research Facility, Manchester, UK.
N L D
NL
Smith
J
J
Hankinson
A
A
Simpson
D W
DW
Denning
P
P
Bowyer
D000328:Adult; D000368:Aged; D001232:Aspergillus fumigatus / Q000302:isolation & purification; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D015870:Gene Expression; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D020662:Guanine Nucleotide Exchange Factors / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008264:Macrophages / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D055732:Pulmonary Aspergillosis / Q000235:genetics* / Q000276:immunology; D011971:Receptors, Immunologic / Q000096:biosynthesis* / Q000235:genetics; D010959:Tissue Plasminogen Activator / Q000096:biosynthesis* / Q000235:genetics; D051201:Toll-Like Receptor 10 / Q000096:biosynthesis* / Q000235:genetics; D051196:Toll-Like Receptor 3 / Q000096:biosynthesis* / Q000235:genetics; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics
C546321:DENND1B protein, human; D053418:Death Domain Receptor Signaling Adaptor Proteins; D020662:Guanine Nucleotide Exchange Factors; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C475955:TLR10 protein, human; C495344:TLR3 protein, human; C408842:TREM1 protein, human; D051201:Toll-Like Receptor 10; D051196:Toll-Like Receptor 3; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C067262:PLAT protein, human; D010959:Tissue Plasminogen Activator
Aspergilloma; Aspergillus fumigatus; CCPA; TLR; aspergillosis; gene expression; genetic susceptibility; immune response; monocyte-derived macrophages