Impaired T cell responsiveness to Interleukin-6 in hematological patients with Invasive aspergillosis

Jose Camargo Galvis, Alyajahan Bhimji, Deepali Kumar, Rupert Kaul, Rhea Pavan, Andre Schuh, Matthew Seftel, Jeffrey H. Lipton, Vikas Gupta, Atul Humar, Shahid Husain

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article numbere0123171
JournalPLoS One
Volume10
Issue number4
DOIs
StatePublished - Apr 2 2015
Externally publishedYes

Fingerprint

Mucormycosis
Aspergillosis
T-cells
aspergillosis
interleukin-6
cell transplantation
Chemotherapy
Hematopoietic Stem Cell Transplantation
Interleukin-6
T-lymphocytes
Stem cells
molds (fungi)
drug therapy
T-Lymphocytes
STAT3 Transcription Factor
Phosphorylation
Fungi
Aspergillus
interferon-gamma
Drug Therapy

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Impaired T cell responsiveness to Interleukin-6 in hematological patients with Invasive aspergillosis. / Camargo Galvis, Jose; Bhimji, Alyajahan; Kumar, Deepali; Kaul, Rupert; Pavan, Rhea; Schuh, Andre; Seftel, Matthew; Lipton, Jeffrey H.; Gupta, Vikas; Humar, Atul; Husain, Shahid.

In: PLoS One, Vol. 10, No. 4, e0123171, 02.04.2015.

Research output: Contribution to journalArticle

Camargo Galvis, J, Bhimji, A, Kumar, D, Kaul, R, Pavan, R, Schuh, A, Seftel, M, Lipton, JH, Gupta, V, Humar, A & Husain, S 2015, 'Impaired T cell responsiveness to Interleukin-6 in hematological patients with Invasive aspergillosis', PLoS One, vol. 10, no. 4, e0123171. https://doi.org/10.1371/journal.pone.0123171
Camargo Galvis, Jose ; Bhimji, Alyajahan ; Kumar, Deepali ; Kaul, Rupert ; Pavan, Rhea ; Schuh, Andre ; Seftel, Matthew ; Lipton, Jeffrey H. ; Gupta, Vikas ; Humar, Atul ; Husain, Shahid. / Impaired T cell responsiveness to Interleukin-6 in hematological patients with Invasive aspergillosis. In: PLoS One. 2015 ; Vol. 10, No. 4.
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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, na{\"i}ve 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.",
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