Review Article C-type lectin receptors and cytokines in fungal immunity Simon Vautier, Donna M. MacCallum, Gordon D. Brown ⇑ Aberdeen Fungal Group, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, UK article info Article history: Available online xxxx Keywords: C-type lectin Cytokine Fungi Innate immunity Signalling abstract Fungi are the cause of opportunistic infections, predominantly in immunocompromised individuals although, primary fungal infections can occur in apparently healthy individuals. Successful host defence requires an effective innate and adaptive immune response. Central to host immune responses are the induction of cytokines; the signals which help to activate the innate immune system and which play a central role in directing the development of pathogen-specific immunity. C-type lectins play a central role in the recognition and shaping of immune responses to fungal pathogens, in part, through the induc- tion and modulation of cytokine responses. Understanding which cytokines induce protective responses to these pathogens and how C-type lectins and other receptors direct cytokine production may allow development of novel antifungal therapies. Here we review the C-type lectins, their influence on cytokine production and subsequent immune responses in antifungal immunity. Ó 2011 Elsevier Ltd. All rights reserved. 1. Introduction 1.1. Fungal infections of man Fungi are ubiquitous in the environment, and we are constantly exposed to fungal spores and cells. These eukaryotic microbes are capable of causing a wide variety of infections, ranging from super- ficial skin and nail infections through to life-threatening invasive diseases (see Table 1). Skin and nail infections are associated with a number of dermatophytes, including Trichophyton spp., Microspo- rum spp. and Epidermophyton spp., causing infections such as ath- lete’s foot and ringworm [1,2]. In addition, human commensal fungi can also cause skin infections, e.g. Candida spp., particularly Candida albicans, which are linked with intetrigo (inflammation of body folds, such as between the digits or under the breasts) and Malassezia spp. are associated with dandruff and pityriasis ver- sicolor (skin rash and pigment changes) [1,2]. Candida spp. are also associated with oral and vaginal thrush and with chronic mucocu- taneous candidiasis, where individuals suffer from recurrent skin, nail and/or mucosal infections [3–5]. Environmental fungi are the major causative agents of fungal lung infections, which are generally self-limiting. However, in immunocompromised individuals these infections can dissemi- nate, leading to much more serious consequences. The major fun- gal species associated with lung infections are Aspergillus species (particularly Aspergillus fumigatus), Cryptococcus neoformans and Pneumocystis jirovecii (see Table 1). In specific regions of North, Central and South America, endemic fungi (Table 1) are also major causes of fungal lung disease [6–9]. The most serious fungal infections are invasive infections, which occur in immunocompromised and severely ill individuals and are associated with high mortality rates [4,10]. Fungi are the causative agents in 20% of all invasive infections in ICU patients [10,11], with 90% of infections caused by C. albicans, Candida glab- rata, Candida tropicalis, Candida parapsilosis and Candida krusei [4,10]. Pulmonary infections can also be the source of invasive fun- gal infection in immunocompromised individuals (see Table 1). It is evident that most fungal infections are opportunistic; therefore, it is vital that the immune system is capable of recogn- ising fungal cells and spores that enter the body and that it mounts an appropriate immune response to deal with the potential threat. This is accomplished through recognition of evolutionary con- served structures, the pathogen associated molecular patterns (PAMPs), on fungi by host cell pattern recognition receptors (PRRs), which include C-type lectin receptors (CLRs) and Toll-like recep- tors (TLRs) [12–18]. In the initial response to fungal infection, innate immune cells (neutrophils and macrophages) phagocytose invading pathogens 1043-4666/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.cyto.2011.08.031 Abbreviations: AIRE, autoimmune regulator; APCs, antigen presenting cells; APECED, autoimmune polyendocrinopathy with candidiasis and ectodermal dys- trophy; BMDC, bone marrow-derived dendritic cells; BMDM, bone marrow-derived macrophages; CLRs, C-type lectin receptors; CTLD, C-type lectin domain; DC, dendritic cell; DC-SIGN, DC-specific ICAM-3 grabbing non-integrin; HIES, hyper IgE syndrome; ITAM, immunoreceptor tyrosine-based activation-like motif; Mincle, macrophage inducible C-type lectin; MR, mannose receptor; PAMPs, pathogen- associated molecular patterns; PRRs, pattern recognition receptors; SNP, single nucleotide polymorphism; TLRs, Toll-like receptors. ⇑ Corresponding author. Address: Aberdeen Fungal Group, Section of Infection & Immunity, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, UK. Tel.: +44 (0) 1224 437355; fax: +44 (0) 1224 555766. E-mail address: Gordon.Brown@abdn.ac.uk (G.D. Brown). Cytokine xxx (2011) xxx–xxx Contents lists available at SciVerse ScienceDirect Cytokine journal homepage: www.elsevier.com/locate/issn/10434666 Please cite this article in press as: Vautier S et al. C-type lectin receptors and cytokines in fungal immunity. Cytokine (2011), doi:10.1016/ j.cyto.2011.08.031