title: Impaired T cell responsiveness to interleukin-6 in hematological patients with invasive aspergillosis.
abstract: Invasive mold infections (IMI) are among the most devastating complications following chemotherapy and hematopoietic stem cell transplantation (HSCT), with high mortality rates. Yet, the molecular basis for human susceptibility to invasive aspergillosis (IA) and mucormycosis remain poorly understood. Herein, we aimed to characterize the immune profile of individuals with hematological malignancies (n = 18) who developed IMI during the course of chemotherapy or HSCT, and compared it to that of hematological patients who had no evidence of invasive fungal infection (n = 16). First, we measured the expression of the pattern recognition receptors pentraxin 3, dectin-1, and Toll-like receptors (TLR) 2 and 4 in peripheral blood of chemotherapy and HSCT recipients with IMI. Compared to hematological controls, individuals with IA and mucormycosis had defective expression of dectin-1; in addition, patients with mucormycosis had decreased TLR2 and increased TLR4 expression. Since fungal recognition via dectin-1 favors T helper 17 responses and the latter are highly dependent on activation of the signal transducer and activator of transcription (STAT) 3, we next used phospho-flow cytometry to measure the phosphorylation of the transcription factors STAT1 and STAT3 in response to interferon-gamma (IFN-γ) and interleukin (IL)-6, respectively. While IFN-γ/STAT1 signaling was similar between groups, naïve T cells from patients with IA, but not those with mucormycosis, exhibited reduced responsiveness to IL-6 as measured by STAT3 phosphorylation. Furthermore, IL-6 increased Aspergillus-induced IL-17 production in culture supernatants from healthy and hematological controls but not in patients with IA. Altogether, these observations suggest an important role for dectin-1 and the IL-6/STAT3 pathway in protective immunity against Aspergillus.
authors.affiliation: Transplant Infectious Diseases, Multi-Organ Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada; Department of Medicine, University Health Network, Toronto, Ontario, Canada.
authors.forename: Jose F
authors.initials: JF
authors.lastname: Camargo
authors.affiliation: Transplant Infectious Diseases, Multi-Organ Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada; Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Alyajahan
authors.initials: A
authors.lastname: Bhimji
authors.affiliation: Transplant Infectious Diseases, Multi-Organ Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada; Department of Medicine, University Health Network, Toronto, Ontario, Canada.
authors.forename: Deepali
authors.initials: D
authors.lastname: Kumar
authors.affiliation: Department of Medicine, University Health Network, Toronto, Ontario, Canada; Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Rupert
authors.initials: R
authors.lastname: Kaul
authors.affiliation: Transplant Infectious Diseases, Multi-Organ Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada; Department of Medicine, University Health Network, Toronto, Ontario, Canada.
authors.forename: Rhea
authors.initials: R
authors.lastname: Pavan
authors.affiliation: Department of Medicine, University Health Network, Toronto, Ontario, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Division of Medical Oncology and Hematology, University Health Network, Toronto, Ontario, Canada.
authors.forename: Andre
authors.initials: A
authors.lastname: Schuh
authors.affiliation: Department of Medicine, University Health Network, Toronto, Ontario, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Division of Medical Oncology and Hematology, University Health Network, Toronto, Ontario, Canada.
authors.forename: Matthew
authors.initials: M
authors.lastname: Seftel
authors.affiliation: Department of Medicine, University Health Network, Toronto, Ontario, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Division of Medical Oncology and Hematology, University Health Network, Toronto, Ontario, Canada.
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Lipton
authors.affiliation: Department of Medicine, University Health Network, Toronto, Ontario, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada; Division of Medical Oncology and Hematology, University Health Network, Toronto, Ontario, Canada.
authors.forename: Vikas
authors.initials: V
authors.lastname: Gupta
authors.affiliation: Transplant Infectious Diseases, Multi-Organ Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada; Department of Medicine, University Health Network, Toronto, Ontario, Canada.
authors.forename: Atul
authors.initials: A
authors.lastname: Humar
authors.affiliation: Transplant Infectious Diseases, Multi-Organ Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada; Department of Medicine, University Health Network, Toronto, Ontario, Canada.
authors.forename: Shahid
authors.initials: S
authors.lastname: Husain
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001228:Aspergillosis / Q000276:immunology* / Q000382:microbiology; D001232:Aspergillus fumigatus / Q000276:immunology / Q000472:pathogenicity; D002097:C-Reactive Protein / Q000378:metabolism*; D002478:Cells, Cultured; D003430:Cross-Sectional Studies; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology*; D020381:Interleukin-17 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000276:immunology*; D037181:Lectins, C-Type / Q000097:blood / Q000378:metabolism; D008875:Middle Aged; D009090:Mucorales / Q000276:immunology / Q000472:pathogenicity; D009091:Mucormycosis / Q000276:immunology* / Q000382:microbiology; D010766:Phosphorylation; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000683:Serum Amyloid P-Component / Q000378:metabolism*; D058504:Th17 Cells / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000097:blood / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000097:blood / Q000378:metabolism; D055815:Young Adult; D000099153:Pentraxins; D000099181:Dectin-1
chemical_list: D002097:C-Reactive Protein; D007371:Interferon-gamma; D020381:Interleukin-17; D015850:Interleukin-6; D037181:Lectins, C-Type; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D000683:Serum Amyloid P-Component; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D000099153:Pentraxins; C546929:CLEC7A protein, human; D000099181:Dectin-1; C508600:IL6 protein, human; C494079:STAT1 protein, human; C494086:STAT3 protein, human; C495342:TLR2 protein, human; C495345:TLR4 protein, human
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