Human Natural Killer Cells Exhibit Direct Activity Against Aspergillus fumigatus Hyphae, But Not Against Resting Conidia

Abstract

Because natural killer (NK) cells kill tumor cells and combat infections, there is growing interest in adoptively transferring NK cells to hematopoietic stem cell recipients. Unfortunately, in humans, the activity of NK cells against Aspergillus species, the major cause of invasive fungal infection in stem cell recipients, are poorly characterized. Our results show that unstimulated and interleukin-2 prestimulated human NK cells kill Aspergillus fumigatus hyphae but do not affect resting conidia. Killing is also induced by the supernatant of prestimulated NK cells and human perforin. The high levels of interferon-γ and granulocyte macrophage colony-stimulating factor produced by prestimulated NK cells are significantly reduced by Aspergillus, indicating an immunosuppressive effect of the fungus. Whereas Aspergillus hyphae activate NK cells, resting, and germinating, conidia and conidia of ΔrodA mutants lacking the hydrophobic surface layer do not. Our results suggest that adoptively transferred human NK cells may be a potential antifungal tool in the transplantation context.

Human NK Cells Display Important Antifungal Activity againstAspergillus fumigatus, Which Is Directly Mediated by IFN-γ Release

“…fumigatus interaction recognized an activity of NK cells against germlings. Although we found that IFN-g can directly inhibit the fungal growth, Schmidt et al (34) implicated perforin as a major effector molecule of NK cell-mediated anti-Aspergillus activity. We believe that the discrepancies between their data and ours can be explained by the different study designs.…”

“…However, our data demonstrate that the NK cell-A. fumigatus interaction does not involve substantial degranulation, which argues against a functional importance of the above mentioned proteins in the antifungal activity of NK cells (34). It is worth noting that our data cannot exclude the involvement of an additional factor, induced by the fungus and secreted by an unknown process.…”

Bioengineering T cells to target carbohydrate to treat opportunistic fungal infection

“…These assays also demonstrated that D-CAR is able to activate proinflammatory and cytolytic machinery such as the perforin/granzyme pathway of genetically modified T cells. The exocytosis of cytolytic granules apparently can disrupt fungal germination directly, as evident from the reports that granzyme-deficient mice are susceptible to IFI (41,42). The production of IFN-γ from the D-CAR + T cells may further augment immunity to IFIs, because pharmacological dosing of recombinant IFN-γ (43) or of IFN-γ derived from CD4 + helper T cells or NK cells has been shown to augment anti-Aspergillus activity (44,45).…”

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“…From the pathogen´s point of view, A. fumigatus produces a variety of proteins, such as proteinases or mycotoxins, all of which are important in the defense mechanisms of the fungus and tissue invasion, as they detoxify antifungal molecules produced by the host or break down the host defense barriers [4]. As we have demonstrated in an earlier study that A. fumigatus decreases the protein concentration of NK cell-derived IFN-γ in the supernatant [5], we investigated the influence of A. fumigatus on the expression of selected genes which are known to play a role in the antifungal activity of NK cells. Given the complex nature of the host-pathogen interaction, we also assessed the response of A. fumigatus to host immunity.…”