Natural killer cell‐mediated damage of clinical isolates of mucormycetes

Abstract

Haematopoietic stem cell transplant (HSCT) recipients are at high risk for mucormycosis, which has a mortality of up to 90%. The adoptive transfer of Natural killer (NK) cells is a promising therapeutic option in order to improve the reconstitution of host immunity after HSCT and to directly combat the fungal pathogen. As a number of fungal pathogens have developed strategies to evade the innate immune system, we investigated the interaction of human NK cells with various clinical isolates of different species of mucormycetes. Our results show that human IL-2 prestimulated NK cells damaged all mucormycetes tested. The extent of the damage depended, at least in part, on the growth curve characteristics of the individual fungal isolate. All isolates decreased the secretion of interferon-γ by NK cells to a similar extent. Our data suggest that NK cells damage a wide spectrum of mucormycetes, but that the antifungal effect is higher if NK cells are administered at an early time point of infection.

The mucormycete–host interface

“…Human monocyte derived dendritic cells recognize β-glucan exclusively expressed on the hyphal surface through the pattern recognition receptor dectin-1 to induce IL-23, IL-1 and TNF-α [15]. Damage and killing is mediated by oxidative means after monocyte or neutrophil attachment to fungal filaments [16-18], through degranulation, and release of cationic peptides or perforin by rabbit and human neutrophils or NK cells, respectively [12,18-20]. Hydrocortisone treatment inhibits neutrophil or macrophage induced hyphal damage [18,21] and macrophages from diabetic mouse have reduced ability to adhere to hyphae [17].…”

“…Hydrocortisone treatment inhibits neutrophil or macrophage induced hyphal damage [18,21] and macrophages from diabetic mouse have reduced ability to adhere to hyphae [17]. Even in healthy hosts, the extent of hyphal damage depends on the extent of fungal biomass [12,22]. …”

Role of microglia in fungal infections of the central nervous system

“…116 Additionally, the adoptive transfer of NK cells is promising alternative therapy that may restore host immunity after HSCT, decreasing the patients' susceptibility to mucormycosis. 115 IL-2 pre-stimulation of NK cells effectively killed a broad range of mucormycetes. Surprisingly, NK cells displayed a reduced production of IFN-g, which is important augmenting the fungicidal activity of macrophages.…”

“…114 Other populations at risk are patients with compromised immunity due to chemotherapy and a known history of haematopoietic stem cell transplantation (HSCT). 115,116 These patients have suppressed expression of Dectin-1 and TLR-2, due to possible polymorphisms, which may facilitate their susceptibility to acquire this fungal infection. In fact, patients with mucormycosis have shown a deficient population of CD4 C T cells that is responsive to IL-6 stimulation.…”

Immune responses to Mucorales growth forms: Do we know everything?

“…11 In addition, natural killer (NK) cells were shown to damage a wide spectrum of Mucorales, but the antifungal effect was higher if NK cells were administered at an early time point of infection. 12 What is the reason of more difficulty to prevent and manage mucormycosis than other mycoses? Is it just because Mucorales are more resistant to commonly used antifungal agents like voriconazole?…”