Candida albicans Dampens Host Defense by Downregulating IL-17 Production

Abstract

IL-17 is one of the key cytokines that stimulate host defense during a Candida infection. Several studies have demonstrated the capacity of Candida albicans to induce a Th17 response. Surprisingly, experiments employing live C. ablicans demonstrated a specific downregulation of host IL-17 secretion in human blood mononuclear cells (PBMCs). By avoiding the direct contact of live C. albicans and PBMCs, we demonstrate that this inhibition effect is mediated by a soluble factor released by live C. albicans. However, this effect is due neither to the releasing of C. albicans pathogen-associated molecular patterns nor to the alteration of different Th cell subtypes. Rather, we found that live C. albicans shifts tryptophan metabolism by inhibiting IDO expression away from kynurenines and toward 5-hydroxytryptophan metabolites. In addition, we show that these latter 5-hydroxytryptophan metabolites inhibit IL-17 production. In conclusion, live C. albicans inhibits host Th17 responses by modulatory effects on tryptophan metabolism.

The role of pattern recognition receptors in the innate recognition ofCandida albicans

“…Five-hydroxytryptophan metabolites inhibit IL-17 production. 193 Thus, live C. albicans may inhibit host Th17 responses, and experiments using live C. albicans, heat-killed C. albicans or PAMPs may lead to different conclusions. Secondly, more in-vivo research data are needed to better understand oral/vaginal candidiasis and host immune responses.…”

“…One more example is that live C. albicans and heat-killed C. albicans may lead to different Th17 responses. 193 In mammalian cells, 2 pathways of tryptophan metabolization have been described. One pathway leads to the L-kynurenine synthesis and thereafter to niacin as the end metabolite.…”

“…The second pathway is mediated by the enzymatic activity of tryptophan hydroxylase, producing 5-hydroxytryptophan, followed by further metabolization into serotonin and melatonin. 193 Under conditions that PBMCs were incubated with C. albicans, live C. albicans can shift tryptophan metabolism away from kynurenines and toward 5-hydroxytryptophan metabolites. Five-hydroxytryptophan metabolites inhibit IL-17 production.…”

Interplay between Candida albicans and the Mammalian Innate Host Defense

“…By inhibiting IDO expression, C. albicans could shift tryptophan metabolism, leading to fewer kynurenines and more 5-hydroxytryptophan metabolites. The increased 5-hydroxytryptophan levels subsequently inhibit host IL-17 production (20).…”

Evolution to a Chronic Disease Niche Correlates with Increased Sensitivity to Tryptophan Availability for the Obligate Intracellular Bacterium Chlamydia pneumoniae

“…Although most reports document pathogen sensitivity to tryptophan depletion, recent studies are finding a role for IDO activity in chronic or persistent disease. In particular, IDOtryptophan-directed immunosuppression is thought to play a role in infections by Leishmania major (90), human immunodeficiency virus (reviewed in reference 91), hepatitis C virus (92,93), human papillomavirus (94), Listeria monocytogenes (95), Mycobacterium tuberculosis (96), Candida albicans (97), and Aspergillus fumigatus (98). Importantly, a recent study investigating the role IDO plays in infections by two protozoal species, T. gondii and L. major, found that IDO facilitates T. gondii clearance and suppresses L. major clearance, highlighting the opposing and pathogen-specific roles that IDO can have in infectious disease (90).…”