Impaired T Cell Responsiveness to Interleukin-6 in Hematological Patients with Invasive Aspergillosis

• Published in: PloS one Vol. 10; no. 4; p. e0123171
• Main Authors: Camargo, Jose F., Bhimji, Alyajahan, Kumar, Deepali, Kaul, Rupert, Pavan, Rhea, Schuh, Andre, Seftel, Matthew, Lipton, Jeffrey H., Gupta, Vikas, Humar, Atul, Husain, Shahid
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 02.04.2015; Public Library of Science (PLoS)
• Subjects: Adolescent; Adult; Aged; Aspergillosis; Aspergillosis - immunology; Aspergillosis - microbiology; Aspergillus; Aspergillus fumigatus; Aspergillus fumigatus - immunology; Aspergillus fumigatus - pathogenicity; C-Reactive Protein - metabolism; Cancer; Care and treatment; Cells, Cultured; Chemotherapy; Complications; Complications and side effects; Cross-Sectional Studies; Cytokines; Ethics; Flow cytometry; Fungal infections; Fungi; Health aspects; Health care networks; Hematology; Hematopoietic stem cells; Humans; Immune system; Immunity; Infections; Infectious diseases; Influence; Interferon; Interferon-gamma - immunology; Interleukin-17 - biosynthesis; Interleukin-6; Interleukin-6 - immunology; Interleukins; Lectins, C-Type - blood; Lectins, C-Type - metabolism; Lymphocytes; Lymphocytes T; Medicine; Middle Aged; Mortality; Mucorales; Mucorales - immunology; Mucorales - pathogenicity; Mucormycosis - immunology; Mucormycosis - microbiology; Oncology; Patients; Pattern recognition; Phosphorylation; Proteins; Receptors; Serum Amyloid P-Component - metabolism; STAT1 Transcription Factor - metabolism; STAT3 Transcription Factor - metabolism; Stem cell transplantation; Stem cells; Th17 Cells - immunology; Toll-Like Receptor 2 - blood; Toll-Like Receptor 2 - metabolism; Toll-Like Receptor 4 - blood; Toll-Like Receptor 4 - metabolism; Transplantation; Transplants & implants; Young Adult; Canada; Grand Island New York; Toronto Ontario Canada; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0123171

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.