Human NK cells display important antifungal activity against Aspergillus fumigatus, which is directly mediated by IFN-γ release.

Despite the strong interest in the NK cell-mediated immunity toward malignant cells and viruses, there is a relative lack of data on the interplay between NK cells and filamentous fungi, especially Aspergillus fumigatus, which is the major cause of invasive aspergillosis. By studying the in vitro interaction between human NK cells and A. fumigatus, we found only germinated morphologies to be highly immunogenic, able to induce a Th1-like response, and capable of upregulating cytokines such as IFN-γ and TNF-α. Moreover, priming NK cells with human rIL-2 and stimulating NK cells by direct NK cell-pathogen contact were essential to induce damage against A. fumigatus. However, the most interesting finding was that NK cells did not mediate anti-Aspergillus cytotoxicity through degranulation of their cytotoxic proteins (perforin, granzymes, granulysine), but via an alternative mechanism involving soluble factor(s). To our knowledge, our study is the first to demonstrate that IFN-γ, released by NK cells, directly damages A. fumigatus, attributing new properties to both human NK cells and IFN-γ and suggesting them as possible therapeutic tools against IA.

Genetic susceptibility to Aspergillus fumigatus infections.

Invasive aspergillosis mostly caused by the opportunistic mould Aspergillus fumigatus is characterized by high morbidity and mortality in risk group patients. Several ethno-pathological factors promote the development and the course of this fungal infection like neutropenia, T-cell depletion, CD34-selected stem cell products, corticosteroid therapy, or cytomegalovirus infections. Furthermore, a growing number of defined single nucleotide polymorphisms affiliated to genes affecting the innate immune response has been described which genetically determine susceptibility to A. fumigatus. Thereby, it concerns a broad band ranging from genes encoding for cytokines or chemokines, their respective receptors to those of toll-like receptors including further genes involved in recognition and defence of pathogens by the innate immune system. Here, we summarize in detail the current knowledge about genetic markers correlated with invasive aspergillosis and their relevance for the developing and outcome of infections with A. fumigatus.

Genetic polymorphisms in the cytokine and chemokine system: their possible importance in allogeneic stem cell transplantation.

Chemokines represent central players of the innate and adaptive immunity and are involved in the regulation of inflammatory events occurring during infectious complications or during graft vs. host disease (GvHD). Patients after allogeneic stem cell transplantation (alloSCT) are at a high risk for the development of acute GvHD or to suffer from fungal infections. Susceptibility to fungal infections and the course of GvHD can be genetically influenced by single nucleotide polymorphisms (SNPs), which regulate expression or biological activity of chemokines, and therefore have an impact on the outcome of invasive aspergillosis and GvHD. High lightened studies of abetting factors for GvHD revealed SNPs in TNFA, IL-6, IL-10, INF-γ, CCL2, CCL5 (RANTES), IL-1Ra, IL-23R, IL-7Ralpha, IL-10RB, and CCR9 genes as prevalent considerable. Furthermore, additional SNPs were described to be significantly associated with fungal infections (Aspergillus fumigatus, Candida albicans), including markers in CCL3, CCL4, CCL20, CXCL2, CXCL8, CXCL10, CCR1, and CCR2. This review summarizes the current knowledge about the growing number of genetic markers in chemokine genes and their relevance for patients after alloSCT.

Immune responses of human immature dendritic cells can be modulated by the recombinant Aspergillus fumigatus antigen Aspf1.

Invasive aspergillosis is a significant cause of morbidity and mortality in patients after stem cell transplantation, in solid organ transplant recipients, and in patients with hematological malignancies. The interactions between human immature dendritic cells (iDCs) and Aspergillus fumigatus antigens are widely uncharacterized. We analyzed the immune response of iDCs to different recombinant A. fumigatus antigens (Aspf1 and Crf1). One of these antigens, the 18-kDa RNase Aspf1, triggered the increased level of expression of genes encoding proinflammatory cytokines and chemokines, and augmented the activation of NFkappaB and the apoptosis of iDCs. Furthermore, by fluorescence microscopy, we could demonstrate that in the first 3 h a major portion of Aspf1 accumulates on the cell surface. Finally, we could show an increased segregation of cytokines and chemokines after the stimulation of iDCs by an Aspf1 deletion mutant strain of A. fumigatus.