IL-27 Induced by Select Candida spp. via TLR7/NOD2 Signaling and IFN-β Production Inhibits Fungal Clearance.
Candida spp. elicit cytokine production downstream of various pathogen recognition receptors, including C-type lectin-like receptors, TLRs, and nucleotide oligomerization domain (NOD)-like receptors. IL-12 family members IL-12p70 and IL-23 are important for host immunity against Candida spp. In this article, we show that IL-27, another IL-12 family member, is produced by myeloid cells in response to selected Candida spp. We demonstrate a novel mechanism for Candida parapsilosis-mediated induction of IL-27 in a TLR7-, MyD88-, and NOD2-dependent manner. Our data revealed that IFN-β is induced by C. parapsilosis, which in turn signals through the IFN-α/β receptor and STAT1/2 to induce IL-27. Moreover, IL-27R (WSX-1)-deficient mice systemically infected with C. parapsilosis displayed enhanced pathogen clearance compared with wild-type mice. This was associated with increased levels of proinflammatory cytokines in the serum and increased IFN-γ and IL-17 responses in the spleens of IL-27R-deficient mice. Thus, our data define a novel link between C. parapsilosis, TLR7, NOD2, IFN-β, and IL-27, and we have identified an important role for IL-27 in the immune response against C. parapsilosis Overall, these findings demonstrate an important mechanism for the suppression of protective immune responses during infection with C. parapsilosis, which has potential relevance for infections with other fungal pathogens.
Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, United Kingdom;
Emmanuel C
EC
Patin
University Dental Hospital, Cardiff and Vale University Health Board, Cardiff CF14 4XY, United Kingdom;
Adam V
AV
Jones
Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, United Kingdom;
Aiysha
0000-0002-6729-2015
A
Thompson
Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, United Kingdom;
Mathew
0000-0002-9280-5281
M
Clement
Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, United Kingdom;
Chia-Te
CT
Liao
Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, United Kingdom;
James S
JS
Griffiths
Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, United Kingdom;
Leah E
0000-0002-0600-9976
LE
Wallace
Department of Veterinary Medicine, University of Cambridge, Cambridge CB3 0ES, United Kingdom;
Clare E
CE
Bryant
Institute of Clinical Microbiology, Immunology and Hygiene, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany; and.
Roland
R
Lang
Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, 24105 Kiel, Germany.
Philip
P
Rosenstiel
Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, United Kingdom;
Ian R
IR
Humphreys
Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, United Kingdom;
Philip R
PR
Taylor
Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, United Kingdom; orrs@cardiff.ac.uk jonesgw6@cardiff.ac.uk.
Gareth W
GW
Jones
Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff CF14 4XN, United Kingdom; orrs@cardiff.ac.uk jonesgw6@cardiff.ac.uk.
Selinda J
0000-0001-8539-7825
SJ
Orr
D000818:Animals; D002175:Candida / Q000502:physiology*; D002177:Candidiasis / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D057131:Immune Evasion; D018836:Inflammation Mediators / Q000378:metabolism; D016899:Interferon-beta / Q000378:metabolism; D064094:Interleukin-27 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology*; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000378:metabolism; D018121:Receptors, Cytokine / Q000235:genetics; D018123:Receptors, Interleukin; D015398:Signal Transduction; D051199:Toll-Like Receptor 7 / Q000378:metabolism*
D016207:Cytokines; C484747:Il27ra protein, mouse; D018836:Inflammation Mediators; D064094:Interleukin-27; D053473:Nod2 Signaling Adaptor Protein; C495945:Nod2 protein, mouse; D018121:Receptors, Cytokine; D018123:Receptors, Interleukin; D051199:Toll-Like Receptor 7; D016899:Interferon-beta