# Fungal Pigments and Their Roles Associated with Human Health
## 4 Interaction of Fungal Pigments with the Host Immune System  
One of the most interesting defense mechanisms of fish may involve non-specific immune responses that have evolved due to their long-term associations with fungi [114]. Specifically, the prevalent colonization of _Rhodotorula mucilaginous_ (a red yeast) in the fish gastrointestinal (GI) tract might have contributed to the stimulation of non-specific mechanisms of host immunoprotection as well as the maturation of the host GI tract [115]. Spectrophotometric analysis in wild fish (_Abramis brana_, _Rutilus rutilus_, _Perca fluviatilis_) indicated the presence of a set of three pigments--\(\beta\)-carotene, torularhodin, and torulene, which are produced by the commensal _Rh. mucilaginous_. In addition to acting as scavengers of free radicals, these fungus-derived pigments are hypothesized to play a role in the immunostimulation of the host via enhanced activation of T lymphocytes, supporting the action of macrophages [116] or antimicrobial activity [115]. For decades, an accumulating body of evidence has revealed that carotenoids or their derivatives are involved in the activation of thymocytes [117], the expression of immune-associated genes [118], and the increase in membrane fluidity [119], which represent vitally important functions in mounting immune responses in animals. Notably, the immunostimulatory effects of carotenoids are thought to be distinct from their antioxidant property [116]. Earlier investigations indicated that \(\beta\)-carotene and the non-provitamin A carotenoids are able to enhance cell-mediated and humoral immune responses in mammals [116]. It is not surprising that \(\beta\)-carotene-producing red yeast _Rh. mucilaginous_ might be beneficial to its hosts, in this case the wild fish, presumably through immuno-stimulation. Given that (i) immunostimulatory effects of carotenoids in animals are thought to be independent of their antioxidant property [116], and (ii) innate immunity relies on effectors which produce cytotoxic molecules that may not only kill pathogens, but also harm host tissues, the mechanisms underlying the roles of carotenoid pigments in the well-being of animals need to be elucidated. Although the functionality of dietary antioxidants in invertebrate immunity is not fully understood, it has been found in vertebrates that carotenoids can scavenge cytotoxic radicals formed during the immune response. Carotenoids may consequently decrease the self-harming cost of immunity. A positive correlation between the effectiveness of the innate immune defense and the levels of circulating carotenoid might therefore be expected. In accordance with this hypothesis, a study using the amphiopod species _Gammarus pulex_ showed that the maintenance and use of the prophenoloxidase system were highly correlated with the carotenoid level in the haemolymph within the natural populations of this crustacean [120]. The enhanced immunity by carotenoids has also been demonstrated in mammals [121] where mice administered _Rhodotorula glutinis_-derived carotenoid could survive for 2 weeks post lethal-dose challenges of pathogenic _Pseudomonas aeruginosa_ and _C. albicans_. This result points to the potential use of fungal carotenoids as food additives or dietary supplements to boost the human immune response against microbial infections. Like carotenoids, melanins are ubiquitously produced by fungi, particularly pathogenic fungi such as _Cryptococcus neoformans_, _Aspergillus fumigatus_, and _Candida albicans_. As described previously,  
Figure 11: The indolic compounds 6-hydroxy-1H-indole-3-carboxaldehyde (**left**) and 6-hydroxy-1H-indole-3-acetamide (**right**) isolated from the fruiting bodies of _Agrocyble cylindracan_ (middle, insert image). mechanics in fungal pathogens contribute to fungal pathogenesis towards mammalian cells [10]. The melanin pigments contribute to antigen masking to circumvent recognition by host immune system and to the survival of fungal pathogens against phagocytosis [122]. For example, phagocytosed _C.