Neutrophil extracellular traps in fungal infection

Abstract

Fungal infections are a continuously increasing problem in modern health care. Understanding the complex biology of the emerging pathogens and unraveling the mechanisms of host defense may form the basis for the development of more efficient diagnostic and therapeutic tools. Neutrophils play a pivotal role in the defense against fungal pathogens. These phagocytic hunters migrate towards invading fungal microorganisms and eradicate them by phagocytosis, oxidative burst and release of neutrophil extracellular traps (NETs). In the last decade, the process of NET formation has received unparalleled attention, with numerous studies revealing the relevance of this neutrophil function for control of various mycoses. Here, we describe NET formation and summarize its role as part of the innate immune defense against fungal pathogens. We highlight factors influencing the formation of these structures and molecular mechanisms employed by fungi to impair the formation of NETs or subvert their antifungal effects.

Keywords: Aspergillus; Candida; Immunology; Neutrophil; Neutrophil extracellular trap (NET).

Figure 1. Neutrophils release NETs in response to C. albicans

A) Scanning electron microscopy images reveal the formation of NETs following a 4 h incubation of human neutrophils with C. albicans. Measurement bars represent 10 μm and 2 μm for images obtained at 2,000 (left) and 10,000x (right), respectively. (B) Propidium iodide (red) staining shows the extracellular DNA of NETs released by human neutrophils upon exposure of human neutrophils to C. albicans.

Figure 2. Neutrophils release NETs during A. fumigatus infection

Immunohistochemistry was performed on bronchioles of mice with invasive pulmonary aspergillosis induced by nasal infection with hyphal filaments. MPO (red) and histone (green) were stained with specific antibodies and fluorescently-labelled secondary antibodies. The nuclear contents of cells are stained with DAPI (blue). In patchy areas NET-associated proteins MPO, histone and DAPI co-localize extracellularly as depicted by superimposition of all three fluorescent channels (A), phase contrast (B), histone (C), MPO (D) and DAPI (E). White arrow indicates direction of epithelial layer. Size bars represent 5 μM.

Figure 3. Induction and inhibition of NET release in response to fungal pathogens based on morphology

C. albicans, C. dubliniensis, and C. glabrata induce NET formation. Yeast forms of C. albicans can inhibit NET release through engagement of Dectin-1 and subsequent induction of phagocytosis. In addition, yeast efficiently scavenge ROS which is required for NET induction. The capsule of C. neoformans inhibits NET release. A. fumigatus hyphae and biofilms trigger NET release. However, A. fumigatus conidia inhibit formation and are engulfed by phagocytosis. Both conidia and yeast forms of P. braziliensis induce NETs.