The Adaptor CARD9 Is Required for Adaptive but Not Innate Immunity to Oral Mucosal Candida albicans Infections

Abstract

d Oropharyngeal candidiasis (OPC [thrush]) is an opportunistic infection caused by the commensal fungus Candida albicans.OPC is common in individuals with HIV/AIDS, infants, patients on chemotherapy, and individuals with congenital immune defects. Immunity to OPC is strongly dependent on the interleukin-23 (IL-23)/IL-17R axis, as mice and humans with defects in IL-17R signaling (IL17F, ACT1, IL-17RA) or in genes that direct Th17 differentiation (STAT3, STAT1, CARD9) are prone to mucocutaneous candidiasis. Conventional Th17 cells are induced in response to C. albicans infection via signals from C-type lectin receptors, which signal through the adaptor CARD9, leading to production of Th17-inducing cytokines such as IL-6, IL-1␤, and IL-23. Recent data indicate that IL-17 can also be made by numerous innate cell subsets. These innate "type 17" cells resemble conventional Th17 cells, but they can be activated without need for prior antigen exposure. Because C. albicans is not a commensal organism in rodents and mice are thus naive to this fungus, we had the opportunity to assess the role of CARD9 in innate versus adaptive responses using an OPC infection model. As expected, CARD9؊/؊ mice failed to mount an adaptive Th17 response following oral Candida infection. Surprisingly, however, CARD9 ؊/؊ mice had preserved innate IL-17-dependent responses to Candida and were almost fully resistant to OPC. Thus, CARD9 is important primarily for adaptive immunity to C. albicans, whereas alternate recognition systems appear to be needed for effective innate responses.

Th17 Inflammation Model of Oropharyngeal Candidiasis in Immunodeficient Mice

“…Consistent to this data, it has been also previously shown that Rag -/-mice clear the primary OPC infection without much immunopathology 27 . Under these conditions, compensatory mechanisms dependent on IL-17A producing innate immune cells have been shown to clear the infection in Rag-/-mice 17,29,30 . Taken together, although IL-17A produced by Th17 cells and neutrophil recruitment are playing a protective role at initial phases of infection, excessive production of TNF-α and other cytokines by Th17 cells, and the continued presence of neutrophils causes exacerbated immunopathology.…”

Adaptive immune responses toCandida albicansinfection

“…19,20,22 The importance of this process in adaptive immune responses to C. albicans can be demonstrated as CARD9 ¡/¡ mice are unable to mount Th17 responses to oral infection. 23 Assembly of the CARD complex leads to activation of the IkB kinase complex which promotes activation and nuclear translocation of the transcription factor NF-kB 22 ( Fig. 1 B).…”

Ecological Approaches to Oral Biofilms: Control without Killing

“…For example, vitamin D and some short chain fatty acids can increase the production of innate defence molecules, such as LL-37, by many cells including the gingival epithelium [McMahon et al, 2011]. Host defences may not need to be present at inhibitory levels but, like exogenously applied antimicrobials, may influence the microbiota at subinhibitory levels; for example, low concentrations of LL-37 have been shown to have antibiofilm activities, including inhibition of biofilm formation, that are distinct from its bactericidal activities [Overhage et al, 2008;Amer et al, 2010;Kai-Larsen et al, 2010;Dean et al, 2011;Bishu et al, 2014]. At subinhibitory levels some host defence factors may also help to eliminate bacteria by acting as adjuncts that increase the effectiveness of antibiotics and other antimicrobials [Yeung et al, 2011;Reffuveille et al, 2014].…”