Abstract
Neutrophils are the most abundant innate immune cells and the first line of defense against many pathogenic microbes, including the human fungal pathogen Candida albicans. Among the neutrophils’ arsenal of effector functions, neutrophil extracellular traps (NETs) are thought to be of particular importance for trapping and killing the large fungal filaments by means of their web-like structures that consist of chromatin fibers decorated with proteolytic enzymes and host defense proteins. Peptidylarginine deiminase 4 (PAD4)-mediated citrullination of histones in activated neutrophils correlates with chromatin decondensation and extrusion and is widely accepted to act as an integral process of NET induction (NETosis). However, the requirement of PAD4-mediated histone citrullination for NET release during C. albicans infection remains unclear. In this study, we show that although PAD4-dependent neutrophil histone citrullination is readily induced by C. albicans, PAD4 is dispensable for NETosis in response to the fungus and other common NET-inducing stimuli. Moreover, PAD4 is not required for antifungal immunity during mucosal and systemic C. albicans infection. Our results demonstrate that PAD4 is dispensable for C. albicans-induced NETosis, and they highlight the limitations of using histone citrullination as a marker for NETs and PAD4−/− mice as a model of NET-deficiency.
Highlights
Candida albicans is one of the most common etiological agents of opportunistic fungal infections that occur predominantly in immunocompromised individuals but can affect healthy individuals, e.g. as a consequence of antibiotic therapy
Neutrophil extracellular traps were first described in 2004 by Brinkmann et al as a novel mechanism used by neutrophils to combat infection by trapping and killing extracellular diseasecausing organisms including large fungal particles such as C. albicans hyphae [12, 17]
Many examples have been reported where neutrophil extracellular traps (NETs) contribute to host defense and/or promote pathologies ranging from sepsis, autoinflammatory and metabolic diseases to cancer [48]
Summary
Candida albicans is one of the most common etiological agents of opportunistic fungal infections that occur predominantly in immunocompromised individuals but can affect healthy individuals, e.g. as a consequence of antibiotic therapy. The development of clinical symptoms depends on both the host immune status and microbiota and on C. albicans virulence traits. C. albicans has the ability to reversibly switch between spherical yeast cells and large filaments called hyphae [2]. C. albicans filamentation is associated with increased expression of virulence factors, including adhesins, invasins, and hydrolytic enzymes that contribute to disrupting epithelial and endothelial barriers [4, 5]. A robust immune response is required to protect the host against C. albicans infections [4, 6].
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