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.
Highlights
Patients with hematological malignancies, those with acute myeloid leukemia, are highly susceptible to invasive mold infections (IMI) during the remission-induction phase of chemotherapy and in cases of refractory disease
We aimed to characterize the immune profile of individuals with hematological malignancies who developed IMI during the course of chemotherapy or following Hematopoietic stem cell transplantation (HSCT), and compared it to that of hematological patients who had no evidence of invasive fungal infection
Detection of fungal antigens such as beta-glucans, galactomannan and zymosan by epithelial and phagocytic cells occurs via pattern recognition receptors (PRRs), which recognize highly conserved structures expressed on the cell wall of invading fungi
Summary
Those with acute myeloid leukemia, are highly susceptible to invasive mold infections (IMI) during the remission-induction phase of chemotherapy and in cases of refractory disease. The percentage of dectin-1-expressing CD14+ cells was significantly reduced in patients with IMI when compared to that of non-IFI hematological patients or healthy controls (66.4 ± 20.8 vs 87.5 ± 8.12 [p = 0.001] or 88.9 ± 7.02 [p = 0.0009], respectively) (S1B Fig).
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