Dectin-1 embraces Candida glabrata

The C-type lectin receptor (CLR) Dectin-1 is important for immune responses against systemic infection by Candida glabrata. This would be the “take-home-message” from the work by Chen and coworkers published in the current issue of Virulence.¹ In there, they compare the relevance of both Dectin-1 and Dectin-2 in the immune responses triggered by C. glabrata in terms of cytokine production, ROS generation or candidicidal activity, together with in vivo cellular outcomes such as myeloid infiltration, Th skewing or tissular fungal burden. It constitutes a remarkable piece of data not only because those responses were analyzed in vitro in 2 different cell types, namely, thioglycolate-elicited macrophages and neutrophils, but also because the fungus was in vivo administered by 2 diverse routes such as intraperitoneal and intravenous injection.

An interesting feature of this work is that the evaluation of both cytokine production in vitro and fungal burden in vivo, was performed at 2 different infectious doses of C. glabrata. In this particular case, it was crucial for a correct interpretation of the role for Dectin-2 in the response against the fungus. High infectious doses revealed a function for this receptor that was not observed at low multiplicity of infection. Indeed, it was only at this high infectious dose when data matched with former literature addressing the relevance of Dectin-2 for host defense during Candida glabrata-induced candidiasis.² An additional level of complexity approached by the authors in this work, was the use of 2 different strains of C. glabrata when studying the in vivo role of both Dectin-1 and Dectin-2. This fact is quite relevant as diverse isolates of the same fungal species can trigger tremendously different responses.³

The relevance of CLRs in antifungal immunity and in particular of Dectin-1, is well established in the field, especially based on the increased susceptibility of humans bearing mutations in this receptor or components of its signaling pathway.⁴ However, in vivo data have been sometimes controversial; Dectin-1 was considered as required⁵ and dispensable⁶ for host defense against Candida albicans, while 2 works claimed that Dectin-1-deficient mice were susceptible⁷ or resistant⁸ to DSS-induced colitis. Reasonable explanations have been proposed to clarify these concerns, such as divergences in mouse backgrounds or differential microbiota composition between animal facilities, respectively. However, we should be aware of these examples, and commit to obtain solid conclusions from our studies. The work by Chen et al. is a good example as it is quite systematic, including as indicated, “double-checked” experiments in terms of cell types used, doses and routes of administration and fungal strains.

Focusing on clinical data, most of fungal infections in humans are mediated by Candida albicans. However, epidemiological studies indicate increasing incidence of non-albicans Candida infections. Among them, although Candida glabrata is the most prevalent, followed by C. parapsilosis and C. tropicalis,⁹ no much immunological studies were available regarding C. glabrata until Chen and colleagues have shed light in this topic.

One of the fundamental pathological characteristic of Candida albicans is its capacity to grow as hyphae. It allows a physical way of penetrating into tissues and to evade intracellular immune responses, but also constitute a strategy to hide highly immunogenic β-1–3 glucans that can be recognized by Dectin-1.¹⁰ Nevertheless, despite C. glabrata is not dimorphic, it alternatively shows a plethora of virulence factors. Among them, we could enumerate its ability of disrupting phagosomal maturation in macrophages, high adherence capacity even onto inanimated surfaces and an intrinsic high resistance to antifungal therapies, specially to azoles.¹¹ All these features may explain why evolution “has not cared much” about exposing high amounts of β-1–3 glucans on the surface of C. glabrata. Actually, the authors discuss that Dectin-1 “confers host higher sensitivity for sensing C. glabrata” based on the high exposition of β-1–3 glucans. But at the same time, the reduced sensitivity observed for Dectin-2 could be due to the thinner layer of mannosylated proteins as these are the conventional ligands for this receptor.¹²

Alternatively, it is well known the capacity of C. glabrata of developing biofilms, maybe, as a way of compensating its inability to grow as hyphae. These complex structures are well-organized communities allowing enhanced adhesion capacity, evade host immune mechanisms and resist antifungal treatments.¹¹ This raises intriguing questions: how does biofilm formation impact on C. glabrata recognition by Dectin-1 and/or Dectin-2? How much does the observed phenotype rely on biofilm development? Considering the relevance of this process, specially related to contaminations of surgical instrumental, it would be of great interest to check in vitro responses to C. glabrata under environmental conditions where biofilm formation is boosted. Otherwise, the analysis of surface expression of epitopes would contribute to understand the potential immune responses (either activating or regulating) triggered by these multicellular structures.

In this work by Chen et al., systemic infection with C. glabrata is modeled by both intraperitoneal and intravenous inoculation. However, this fungus generates also mucocutaneous infections.¹¹ In these latter conditions, IL-17 production either by Th17 cells, γδ T cells or type 3 innate lymphoid cells is a critical component of the immune response (greatly reviewed in¹³). In this line, a careful analysis of the provided data indicates that, although no major defects were observed in Dectin-2-deficient mice to a systemic low dose of C. glabrata, this inoculation was not innocuous: IL-17 production during splenocytes recall responses was diminished, even to a deeper extent than in the absence of Dectin-1. Interestingly, different myeloid cell populations are responsible for specific Th responses at mucosae in response to Candida.¹⁴ That notion opens the possibility that the prevalence of signals triggered by Dectin-1, Dectin-2 or even other receptors in response to C. glabrata, could be diverse dependent on the site of infection and the cells involved in that response. Overall, these data suggest a potential role for both receptors during C. glabrata-triggered mucocutaneous infections that needs further investigation.

Nowadays, we have much information about the pathophysiology of Candida albicans.¹⁵ However, as the increased incidence of non-albicans candidiasis constitute a major clinical challenge, we need studies about the immune responses triggered by species such as C. parapsilosis and C. tropicalis. Chen and colleagues has shown us the path to follow.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Acknowledgments

Thank you to David Sancho for his continuous support and confidence. My gratefulness to Paula Saz for her critical reading of the manuscript.

Funding

Carlos del Fresno is supported by AECC Foundation as recipient of an “Ayuda Fundación Científica AECC a personal investigador en cáncer.” The CNIC is supported by the Spanish Ministry of Economy and Competitiveness (MINECO) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015–0505).