Despite being the most prevalent fungal genera in the human microbiome,
Malassezia are little known outside the field of dermatology.
Malassezia were first described in 1889, yet it took nearly a century to firmly establish their role in dandruff and seborrheic dermatitis (
47). This delay can be attributed to
Malassezia's difficulty growing in culture (they require just the right concentration of certain lipids) (
48), their extremely high prevalence on the skin (~100% throughout life) (
49), and their resistance to fungicides (commonly used antifungal drugs do not completely eradicate
Malassezia and their populations rebound once such treatments are discontinued) (
50). About 50% of adults have first-hand experience with
Malassezia-associated symptoms: they use antifungal shampoo to keep their dandruff under control, and whenever they switch back to normal shampoo,
Malassezia and dandruff return (
47).
Until very recently, it was believed that
Malassezia were restricted to the skin, except in rare immunocompromised or lipid-rich parenteral nutrition cases (
34,
51). Due to improved microbe detection techniques, many groups now report finding
Malassezia within the body of both healthy adults and immunocompetent patients with various ailments (
14–
16,
23–
25,
33,
52–
61).
Malassezia's potential role in diseases of internal organs is just coming to light (
19,
54,
62–
64). It is important to note that
Malassezia's presence is not synonymous with disease: in the vast majority of individuals,
Malassezia colonize the body without causing symptoms. This means detecting
Malassezia in a given organ is far from sufficient to prove their involvement in diseases of that organ. Additional lines of evidence are necessary to implicate them, for example the efficacy of antifungal drugs in treating the disease, immunological evidence (such as antibodies against
Malassezia) and genetic evidence (such as genes affecting
Malassezia's lipid supply or the immune response against fungi).
Since
Malassezia are not well-known in the field of neurodegenerative disorders, this section is included as a primer on
Malassezia's suspected role in SD, acquired immune deficiency syndrome (AIDS), Crohn's disease (CD), spondyloarthritides (SpA), and MS. Each of these conditions is informative for PD.
Malassezia Are a Necessary Factor in Seborrheic Dermatitis
Malassezia's role in SD is now generally accepted (
29,
42,
43,
50). Given the right conditions,
Malassezia over proliferate on the skin (
65), resulting in SD—though specific mechanisms are still open to debate (
29,
42,
43,
50). Most SD cases respond well to topical fungicides which reduce
Malassezia populations on affected patches of skin to levels tolerated by patients (
29,
42,
43).
SD occurs mainly in lipid-rich skin regions, especially the face, trunk and scalp (
29,
42,
43).
Malassezia are lipid-dependent fungi: they lack key lipid metabolism genes (including fatty acid synthase, stearoyl-CoA desaturase, and enoyl-CoA isomerase), and thus depend on host lipids for survival (
48). Skin lipid production varies during our lifetime, with a peak in the first year of life, followed by a second peak in adolescence (
66–
68): production is depressed during the rest of childhood, which corresponds to the period of lowest SD risk (
69). In adults, the risk of SD increases substantially with age (
69). This is unexpected because skin lipid levels slowly decline with age (
67), so
Malassezia should have increasing difficulty securing lipids in the elderly.
Azathioprine and cyclosporin, two immunosuppresive drugs which target T cells, substantially increase SD risk (
39). Similarly, CD4+ T cell counts are inversely associated with SD risk and severity in AIDS patients (
29). Peripheral blood mononuclear cells (PBMC) from SD patients produce less IL-2 and interferon gamma (IFNγ) when exposed to
Malassezia antigens as compared to age-matched controls (
70), suggesting a weak type 1 helper T cell (Th1) response against
Malassezia is a characteristic of SD. In healthy individuals, thymic involution reduces naive T cell production, which results in a slow decline in T cell efficacy over our lifespan (
71). This can be observed in part by measuring T cell receptor (TCR) diversity (
71,
72). T cell immunosenescence can explain why SD risk increases with age, despite declining skin lipids. SD seems to be mainly due to the combination of ample lipids (
29,
42,
43) and weak T cell-mediated control (
70,
73,
74) of
Malassezia, which together allow this fungus to over proliferate on the skin.
Seborrheic dermatitis (SD) is a well-known symptom associated with PD: PD patients have ~50% SD prevalence, while controls only have ~3% prevalence (
44,
45). Though these are the most frequently cited figures, they are based on old studies whose accuracy has drawn criticism (
75). We only found one recent study which measured the association between PD and SD (
46). It reported that SD increases the risk of a
subsequent PD diagnosis (OR = 1.69, 95% CI 1.36, 2.1;
p < 0.001). This association remained significant when the SD diagnosis was made at least 5 years before the PD diagnosis, suggesting PD-associated treatments or behavior cannot explain it (
46). This study reported an SD diagnosis rate of 4% prior to a PD diagnosis, as compared to 2.5% for age matched controls (
46). This low rate of association indicates factors predisposing to SD and PD are mostly different. Of note, this report (
46) is only available as an abstract and has not been published as a peer-reviewed article. Specific mechanisms underlying the association between SD and PD are not known (
75). Nonetheless, this association suggests that mechanisms allowing
Malassezia to over proliferate and cause SD (ample lipids and T cell immunosenescence) should be thoroughly investigated as possible mechanisms underlying PD as well.
Malassezia Are a Necessary Factor in Crohn's Disease and Spondyloarthritides
Spondyloarthritides (SpA) are a group chronic immune-mediated diseases mainly driven by alpha beta T cells recognizing intracellular peptides through HLA-B*27 presentation (
62,
83). Affected organs include the spine, joints, skin, eyes, gut, and prostate (
62). Historically, isolated inflammation of the eyes, gut, and skin—respectively acute anterior uveitis, inflammatory bowel disease (Crohn's disease [CD] and ulcerative colitis) and psoriasis—were considered separate diseases unrelated to SpA. However, SpA, acute anterior uveitis, inflammatory bowel disease and psoriasis run together in families (
84), and share many polymorphisms in genes controlling T cell activation (
85), strongly suggesting that they are the same immunological pathology (
84). In particular, the fact that HLA-B*27 increases the risk of each disease strongly suggests the same antigens are being targeted (
62). Varied lines of evidence support the presence of an elusive necessary intracellular fungal infection in each affected organ, which is efficiently detected by HLA-B*27 and CARD9 (
62). CARD9 is an essential signaling protein for fungal immunity: homozygous loss-of-function CARD9 mutations cause severe mycoses (
37). CARD9 polymorphisms are associated with inflammatory bowel disease and SpA (
62,
64). Oral antifungal drugs are effective in psoriasis (
86–
89), psoriatic arthritis (
89,
90), and likely in Crohn's disease as well (
91).
In inflammatory bowel disease and psoriasis, strong evidence points to
Malassezia as being the causative genus (
62). Enteric
Malassezia is strongly associated with CD (
54,
64) and ulcerative colitis (
63). Immune recognition of
Malassezia occurs specifically through CARD9 in the gut, and knocking out CARD9 in mice abrogates colitis symptoms following exposure to
Malassezia (
64). In CD, CARD9 risk alleles increase PBMC secretion of tumor necrosis factor alpha (TNF-α) following
Malassezia antigen challenges (
64). Antibodies against
Malassezia are associated with CD (
64) and psoriasis (
92,
93). Applying lysed
Malassezia to the skin provokes psoriasis lesions in susceptible individuals (
94). The only known fungus which is commonly present in the gut (
61) and on the skin (
49), and thus can explain why Crohn's patients develop psoriasis during vedolizumab treatment (
95), is
Malassezia. Finally, PBMCs in psoriasis react strongly to
Malassezia antigens (
96). These data suggest that a dysregulated immune response against
Malassezia in the gut is causative in CD (
64).
CD and SpA provide three key insights for PD. First, they demonstrate that
Malassezia can cause diseases of internal organs in genetically predisposed individuals. Second, the increased risk of psoriasis in overweight individuals (
97–
100), and the increased risk of CD in carriers of certain
LRRK2 alleles (
101,
102) are most simply explained by enhanced lipid availability (
103) which promotes
Malassezia's growth by supplying it with lipids [the same
LRRK2 alleles increase PD risk (
101,
102)]. Third, intracellular melanin reminiscent of neuromelanin (
104) is associated with inflammation of the prostate (
104–
106). Though indigenous production of melanin by human cells has been proposed as an explanation (
104), a second possible origin would be from
Malassezia which have colonized the prostate and CNS.
Malassezia produce DOPA-melanin from L-DOPA (
107). Both prostate epithelial cells and dopamine neurons contain intracellular lipid droplets which can fulfill
Malassezia's requirement for lipids.
