Species-specific recognition of Aspergillus fumigatus by Toll-like receptor 1 and Toll-like receptor 6.
BACKGROUND
Aspergillus fumigatus causes invasive aspergillosis, a potentially fatal infection in oncohematological patients. Innate immune detection of A. fumigatus involves Toll-like receptor (TLR) 4 and TLR2, which forms a heterodimer with either TLR1 or TLR6. The role of those coreceptors in Aspergillus sensing is unknown.


METHODS
Cytokine production was measured in bone marrow-derived macrophages (BMDMs) from wild-type (WT) and TLR-deficient mice after incubation with a WT and an immunogenic RodA-deficient (ΔrodA-47) strain of A. fumigatus and in lungs from these mice after intranasal mold inoculation. Aspergillus fumigatus-mediated NF-κB activation was measured in HEK293T cells transfected with plasmids expressing mouse or human TLRs.


RESULTS
Bone marrow-derived macrophages from TLR1- and TLR6-deficient mice produced lower amounts of interleukin 12p40, CXCL2, interleukin 6, and tumor necrosis factor α than BMDMs from WT mice after stimulation with A. fumigatus. Lungs from TLR1- and TLR6-deficient mice had diminished CXCL1 and CXCL2 production and increased fungal burden after intranasal inoculation of ΔrodA A. fumigatus compared with lungs from WT mice. ΔrodA strain-mediated NF-κB activation was observed in HEK293T cells expressing mouse TLR2/1, mouse TLR2/6, and human TLR2/1 but not human TLR2/6.


CONCLUSIONS
Innate immune detection of A. fumigatus is mediated by TLR4 and TLR2 together with TLR1 or TLR6 in mice and TLR1 but not TLR6 in humans.
Department of Medicine, University of Lausanne, Switzerland.
Ivana
I
Rubino
Alix
A
Coste
Didier
D
Le Roy
Thierry
T
Roger
Katia
K
Jaton
Michael
M
Boeckh
Michel
M
Monod
Jean-Paul
JP
Latgé
Thierry
T
Calandra
Pierre-Yves
PY
Bochud
D000818:Animals; D001228:Aspergillosis / Q000235:genetics; D001232:Aspergillus fumigatus / Q000472:pathogenicity*; D054426:Chemokine CXCL2 / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate; D053762:Interleukin-12 Subunit p40 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D013045:Species Specificity; D051194:Toll-Like Receptor 1 / Q000378:metabolism*; D051216:Toll-Like Receptor 6 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; D053762:Interleukin-12 Subunit p40; D015850:Interleukin-6; D016328:NF-kappa B; C495369:Tlr6 protein, mouse; D051194:Toll-Like Receptor 1; D051216:Toll-Like Receptor 6; D014409:Tumor Necrosis Factor-alpha