Immunological interactions with fungal melanin

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This entry is adapted from the peer-reviewed paper 10.3390/jof7040264

Melanins are ubiquitous complex polymers that are commonly known in humans to cause pigmentation of our skin. Melanins are also present in bacteria, fungi, and helminths.

melanin fungus yeast immune response

1. Introduction

Melanins are a family of structurally complex dark pigment polymer present in all biological kingdoms ^[1]. The polymer is made up of covalently linked indoles, but the overall structure is granular; however, detailed structures are not well characterized because it is a collection of polymers with mixed pre-indole structures ^[2]. Moreover, melanins are amorphous and are not suitable for study by crystallography or cryo-electron microscopy, which has led to complicated efforts to solve the structure of these natural pigments. Mammalian melanin biogenesis happens by oxidation of L-tyrosine via tyrosinase in melanocytes, which are neural crest-derived dendritic cells ^[3]^[4]. However, melanins in bacteria, fungi, and helminths are produced through the polyketide synthase (PKS) pathway or catalyzed by phenoloxidase ^[5].

2. Melanin Synthesis

Fungi synthesize melanin via two main pathways, namely 1,8-dihydroxynaphthalene (DHN) and l-3,4-dihyroxyphenylalanine (L-DOPA) (Figure 1 and Table 1). In the DHN pathway, 1,3,6,8-tetrahydroxynaphthalene (1,3,6,8-THN) is first synthesized through PKS, which is a multi-domain enzyme complex that produces polyketides. Polyketides are products derived from acetyl-CoA or propionyl-CoA with malonyl-CoA or methylmalonyl-CoA. The condensation reactions are driven by decarboxylation, yielding a beta-keto functional group ^[6]. This is then followed by reduction and dehydration reactions that eventually produce DHN. It is the polymerization of DHN that leads to the formation of melanin ^[5]^[7]^[8]. Polyketides are a class of secondary metabolites mainly produced in bacteria, fungi, and plants, and they serve very different purposes in our society ^[9]. Polyketides such as macrolide, tetracycline, and amphotericin antimicrobials serve tremendous value, while aflatoxin can be lethal to mammals ^[10]^[11].

Figure 1. Current knowledge of melanin synthetic pathways in fungi.

Table 1. Representative fungi and the types of melanin they produce ^[12]^[13]^[14]^[15].

Species	Isolate Environment	Melanin Types
Aspergillus fumigatus	Clinical	DHN and pyo-melanin
Aspergillus niger	Industrial fermentation	DHN and L-DOPA
Blastomyces dermatitidis	Clinical	DHN
Candida Albicans	Clinical	L-DOPA
Cryptococcus neoformans	Clinical	L-DOPA
Histoplasma capsulatum	Clinical	DHN and L-DOPA
Paracoccidioides brasiliensis	Clinical	DHN and L-DOPA
Fonsecaea monophora	Clinical	DHN and L-DOPA
Fonsecaea pedrosoi	Clinical	DHN
Sporothrix schenckii	Clinical	DHN

Abbreviations: DHN is 1,8-dihydroxynaphthalene and L-DOPA is l-3,4-dihyroxyphenylalanine.

The L-DOPA pathway is similar to mammalian melanin biosynthesis, where the pathway typically uses either L-DOPA or tyrosine as starting molecules. If the pathway starts with tyrosine, tyrosinase will perform a two-step oxidation, turning tyrosine into dopaquinone. Similarly, laccase is the enzyme responsible for converting L-DOPA into dopaquinone. Dopaquinone is then turned into leucodopachrome (cyclodopa) and then oxidized to dopachrome. Dopachrome then goes through tautomerization to form dihydroxyindoles, which are simultaneously oxidized and polymerized to produce DOPA melanin ^[8].

3. Cryptococcus neoformans

C. neoformans is one of the most well studied pathogens for melanization (Figure 2). Cryptococcus neoformans is unique among pathogenic fungi as it solely relies on the L-DOPA pathway and requires exogenous phenolic substrates to form melanin. After the polysaccharide capsule, melanin is the second most important virulence factor in C. neoformans as it has been calculated as contributing to 14% of the pathogen’s total virulence ^[16]. This notable aspect of cryptococcal melanization has led to extensive study of this polymer in Cryptococcus spp. ^[17]. Other species can produce melanin using endogenous compounds or exogenous substrates, and some can produce more than one type of melanin ^[12]^[18]^[19].

Figure 2. Cryptococcus neoformans melanin “ghosts” obtained from lungs of infected mice as described in ^[20]. The red arrows show bud scars on the melanin.

In the early 1980s, Kwon-Chung et al. produced melanin-deficient strains (Mel⁻) via UV irradiation and observed that the mutants lacked virulence as the cells were cleared from mouse organs, whereas wild-type (WT) cells expanded in numbers, especially in the brain ^[21]. The same study showed that Mel⁻ mutants were defective in the active transport system for diphenolic compounds and phenoloxidase, which is the first enzyme needed in the L-DOPA melanogenesis pathway. A subsequent study confirmed that the loss of phenoloxidase activity was responsible for the Mel⁻ mutant phenotype ^[22]. Williamson next discovered that laccase, a phenoloxidase, was encoded by the lac1 gene ^[23]. Laccase was linked to C. neoformans virulence in vivo through disruption of the 5′ end of the lac1 gene ^[24]. Interestingly, C. neoformans has two laccase genes, where lac2 is 75% similar to lac1, but basal transcript levels of lac2 are much lower, and mutation of the gene only induced a mild delay in melanin formation ^[25].

4. Aspergillus fumigatus

A. fumigatus is another pathogenic fungus that undergoes melanization, and pigment formation in this species has been the subject of extensive investigation. 1,8-dihydroxynaphthalene (DHN) melanin is the major melanin found in A. fumigatus ^[26]. A set of six genes are needed for melanin synthesis: pksP, ayg1, arp2, arp1, arb1, and arb2, ordered from upstream to downstream ^[27]. Melanin from A. fumigatus has many similarities to melanin from C. neoformans, as both provide protection from ultraviolet light and scavenge ROS generated by phagocytes ^[28]. Albino conidia incubated with phagocytes induced a 10-fold increase in ROS production compared with WT, which suggests that the melanin increased ROS scavenging abilities in the WT conidia. Moreover, the albino mutants were more effectively killed by monocytes than wild-types ^[29].

Melanin regulates host pro-inflammatory cytokine responses by physically masking fungal pathogen-associated molecular patterns (PAMPs) from immune recognition such as that observed by the rodlets layer. Chai et al. demonstrated that albino conidia were able to generate much higher IL-6, IL-10, and TNF-α levels compared to WT. IL-6 and IL-10 had roughly 12-fold and 5-fold higher levels, respectively. The authors pinpointed that albino conidia had β-glucan and other PAMPs such as mannans more readily available to bind to dectin-1, Toll-like receptor 4 (TLR4) and Mannose receptors on peripheral blood mononuclear cells (PBMCs) ^[30]. As conidia mature, they swell and germinate, and this process exposes β-1,3-glucan on their surface, which induces an immune response ^[31].

Jahn et al. observed that ΔpksP melanin-deficient conidia were more effectively phagocytosed and killed by macrophages when compared with WT conidia ^[32]. Thywissen et al. next demonstrated that the albino ΔpksP mutant conidia had a 3.5-fold increase in vacuolar-type ATPase-dependent phagosomal acidification observed in alveolar and monocyte-derived macrophages (~20% acidified conidia vs. 70%). There were virtually no acidified phagosomes containing WT conidia in granulocytes, but ~50% in the mutant group. The pH within the mutant-containing phagolysosome was 5, while the WT had a pH of 6, and the lower pH results in more effective actions by phagosomal enzymes. Interestingly, synthetic DOPA melanin did not prevent acidification, only DHN melanin did ^[33]. However, among Aspergillus spp., A. flavus was the most effective in suppressing acidification, closely followed by A. fumigatus. Microtubule-associated protein 1A/1B-light chain 3 (LC3)-associated phagocytosis (LAP) is a non-canonical autophagy pathway that is linked to certain pattern recognition receptors that trigger phagosome formation ^[34]. A. fumigatus melanin inhibits calcium-calmodulin signaling on the protein Rubicon, a key regulator in the LAP pathway ^[35]^[36], and Rubicon directly interacts with the p22phox subunit and facilitates NADPH oxidase activation during phagocytosis ^[37]. Melanin ultimately blocks the p22phox NADPH oxidase subunit from localizing on the phagosome membrane, thus blocking the assembly of the oxidase complex. Melanin’s effect on the NADPH oxidase complex is conserved in A. nidulans as well ^[38].

The effects of melanin vary on different immune cells. Dendritic cells (DCs) are not stimulated by A. fumigatus melanin. Bayry et al. demonstrated that DCs failed to produce cytokines TNF-α, IL-1β, IL-6, and IL-10 in response to melanized A. fumigatus conidia, and DCs treated with WT melanin ghost also failed to activate T cells ^[39]. The group interestingly found that ΔpksP, Δayg1, and Δarp2 mutants increased different amounts of acetyl-CoA, malonyl-CoA, and 1,3,6,8-THN, respectively. These mutants displayed altered cell walls with unmasked surface structures and were able to activate DCs.

Mammals have evolved various systems to combat melanized fungal pathogens. On the surface of mouse endothelial cells, there is a melanin-sensing C-type lectin receptor (MelLec) that recognizes DHN melanin in the conidial spores of A. fumigatus and other DHN-melanized fungi, such as Cladosporium cladosporioides and Fonsecaea pedrosoi ^[40]. The expression of this C-lectin is essential for protection against disseminated aspergillosis, and albino mutants are not recognized by the receptor. Macrophages change their metabolism in the presence of melanin, especially glycolysis metabolism, which is required for defense against Aspergillus. Goncalves et al. elucidated that DHN melanin blocks endoplasmic reticulum calcium/calmodulin signaling, which activates glycolysis and mammalian target of rapamycin (mTOR)-mediated defense against Aspergillus conidia ^[41]. Consequentially, this impairment of glycolysis, mediated by mammalian target of rapamycin (mTOR) and hypoxia-inducible factor 1 subunit alpha (HIF-1α), decreases macrophages’ conidicidal ability by lowering ROS concentration and inflammatory cytokines IL-1β, IL-6, IL-17A, TNF-α, and IFN-γ production ^[42].

A. fumigatus can be cleared by activating the complement system ^[43]^[44]. Tsai et al. further demonstrated that disruption of the arp1 gene leads to increased C3 deposition on the conidial cell surface ^[45]. Similarly, disrupting alb1/pksP that encodes polyketide synthase resulted in a significant increase in C3 binding on conidial surfaces, with an expected increase in phagocytosis by neutrophils and a decrease in virulence ^[26]^[46]. Direct binding of C3 fragments in normal human serum has been shown with A. niger melanin ^[47].

5. Other Melanotic Fungi and Their Interactions with the Immune System

Fonseca spp. are causative agents of chromoblastomycosis, and these fungi produce large quantities of melanin. Melanized Fonsecaea monophora and cell wall-containing extracted melanin significantly decrease the expression of inducible nitric oxide synthase gene and the production of nitric oxide and enhanced non-protective Th2 responses ^[48]. Macrophages infected with pigmented F. monophora enhanced the differential expression of genes related to immune responses, including the MAPK signaling pathway, demonstrating how melanization modifies pathogenesis ^[49]. As with C. neoformans and A. niger melanin, melanized Fonsecaea pedrosoi was quickly labeled with C3, C4, and C9 complement components ^[50].

Several endemic dimorphic pathogenic fungi produce melanin, including Histoplasma capsulatum ^[51], Paracoccidoides spp. ^[52], Coccidioides immitis ^[53], Blastomyces dermatitidis ^[15], and Talaromyces marneffei ^[54]. Melanin production is associated with pathogenesis in Paracoccidioides spp. through complex processes that extend beyond pigment production. Different Paracoccidioides species resist phagocytosis of yeast cells by macrophages, and this effect is associated with the degree of melanization in each strain ^[55]^[56]. Melanized P. brasiliensis is also highly resistant to NO, ROS, hypochlorite, and H₂O₂ ^[57]. A recent proteomic analysis comparing melanized and non-melanized P. brasiliensis and P. lutzii revealed that melanization leads to an abundance of virulence-associated proteins, including heat-shock proteins, vesicular transport proteins, adhesins, superoxide dismutases, proteases, and phospholipases, which further underscores the complex mechanisms that occur along with melanin production to subvert the host ^[58]. As with cryptococcosis, melanin-binding antibodies are generated during murine as well as human infection with P. brasiliensis ^[55].

T. marneffei (formerly Penicillium marneffei) also utilizes melanin to avoid host defenses. Remarkably, the T. marneffei genome has 23 polyketide synthase genes and additional non-ribosomal polyketide synthase hybrid genes ^[59]. Mutants unable to form the polymer are more sensitive to antifungals, H₂O₂, and sodium dodecyl sulfate (SDS). Furthermore, melanized cells were significantly more resistant to phagocytosis and killing compared to melanin-deficient mutants ^[60]. A second study corroborated the capacity of melanized fungal cells to resist antifungals ^[61]. There is an interesting link to melanin in T. marneffei with tyrosine catabolism, which is essential for survival in the host cells ^[62].

Melanin is well described in Sporothrix spp., and the production of the polymer is closely linked to virulence ^[13]^[63]^[64]. Melanization of S. globosa leads to a reduction in antigen presentation by macrophages and facilitates the dissemination of the pathogen ^[65]. Melanin formation has been linked to increased dissemination in several Sporothrix species ^[66]. However, melanization of some S. schenckii strains may, instead, induce the formation of granuloma, which facilitates the survival of the yeast ^[67]. Melanin production in Sporothrix complex species is protective against diverse antifungal compounds ^[68]^[69].

Melanin is purported to be a major factor in the pathogenicity of Mucorales spp. A recent paper from the Ibrahim laboratory identified compounds that could selectively inhibit eumelanin production by Rhizopus sp. ^[70]. Moreover, the inhibition of melanin by one blocking compound, UOSC-2, led to the formation of spores that were more efficiently phagocytosed and killed in mouse lungs compared to melanized spores, and the albino spores were similarly more efficiently killed by human macrophages, verifying the importance of melanin in protection against host effector responses against this pigmented species.

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