Human immunity to fungal infections

The burden of fungal diseases is increasing globally. Medical advancements, emergence of novel fungal pathogens, rising antifungal resistance, and the creeping expansion of known species into new ecological spaces have increased human-fungal encounters that threaten health. The pipeline for new antifungal agents had stagnated, although promising drug developments have occurred recently. Nonetheless, complementary therapeutic strategies are needed: Rather than focusing on treatments that target fungi, a novel approach would be to engage the human immune system’s intrinsic ability to detect and eliminate these opportunistic infections. This host-directed immunotherapy strategy has proved successful in the field of oncology; it may be particularly important for mycoses refractory to conventional drug therapies. However, to drive this treatment paradigm shift, a deeper understanding of those essential, nonredundant human immunological pathways that kill, control, or capitulate to fungi is needed. This is especially challenging because it requires integrating the “malbolge” (an esoteric language, but also a circle of hell) of human molecular immunology into the field of medical mycology.

Fungi are environmental saprophytes or commensal organisms that diverged from animals and plants roughly 1.5 billion years ago (Wang et al., 1999). That they do not regularly cause disease in their respective hosts indicates the importance of host defenses during these regular encounters. Species-specific differences in susceptibility/resistance/tolerance to fungi in plants and animals determine their decimation or survival (Table 1). In agriculture, this has led to farming practices breeding more resilient crops. In wildlife, coevolution has rendered some species less susceptible to fungal threats. The underlying principle in both is that biological resistance can be modified to favor the host.

While causing disease is not essential for the fungal life cycle, it is remarkable that each fungus can produce various distinct syndromes in humans. Some fungal diseases predominate modern mycology due to their acute, life-threatening nature, iatrogenic context, and clinical prevalence; our understanding of their immunopathophysiology is fairly advanced, providing better prognostic clarity and management strategies. In contrast, other syndromes are long-recognized, but for which the immune determinants of susceptibility and disease outcome have remained elusive. Still, other mycoses remain obscure, overlooked because of their geographical isolation or sporadic and unusual clinical presentations. These lesser-understood mycoses typically occur in the absence of iatrogenesis (i.e., they occur in “natural” settings). Many excellent reviews on fungal pathogenesis (Brown et al., 2024; Whitehead et al., 2024; Lionakis et al., 2023; Griffiths et al., 2021; Desai and Lionakis, 2018; Köhler et al., 2014; Jensen et al., 2024; Kordana et al., 2025; Mills et al., 2024; Kirkland and Fierer, 2018) and on host genetic polymorphisms associated with increased risk of some invasive fungal diseases (IFD) in the immunosuppressed setting exist (Carvalho et al., 2010; Campos et al., 2019; Smith and Denning, 2014; Gow and Netea, 2016; Lionakis, 2019, 2023; Merkhofer and Klein, 2020). This review complements those by focusing on human fungal syndromes “in natura,” updating previous reviews on fungal diseases in inborn errors of immunity (Holland and Vinh, 2009; Puel et al., 2012; Pilmis et al., 2016; Li et al., 2017; Lionakis et al., 2014; Puel, 2020; Ochoa et al., 2020; Vinh, 2023, 2024) and highlighting immunological lessons learned from studying the genetic and molecular factors driving these phenotypes (Fig. 1). These insights provide a roadmap for rational host-directed immunotherapy, precision public health interventions, and the study of enigmatic fungal diseases.

The discovery of the majority of immunological responses to fungal infections stems from the use of animal platforms, primarily the mouse, for experimental studies. Although numerous pivotal insights have emerged from such work, this section will focus exclusively on those that lay the foundation for understanding human antifungal immunity discussed subsequently.

Mice became a common tool for studying candidiasis in the 1950s due to their small size, low cost, and suitability for large-scale production. However, Candida albicans and other candidal species are neither natural commensals nor pathogens of the conventional laboratory mouse (Huppert et al., 1955; Phillips and Balish, 1966). Because of the relative resistance of small laboratory animals to candidal infection, large fungal doses through different inoculation routes (e.g., intraperitoneal, intravenous, intracerebral, and intracardiac) were needed to produce high but modifiable death rates. Initial uses of the mouse platform in candidiasis focused on how antimicrobial agents or steroids affected C. albicans growth in vivo to understand the elevated incidence of invasive candidiasis (IC) in patients receiving these treatments, highlighting its use as a model of clinical disease (Huppert et al., 1955).

One of the earliest use of the mouse to study fungal immunology was to determine if prior infection could induce protection against subsequent homologous or heterologous infection (Dobias, 1964; Mourad and Friedman, 1961, 1968; Soles et al., 1967). These papers confirmed that immunity could be generated: While the underlying mechanisms were not yet elucidated, the data suggested that the protective effect was cellular in basis rather than serologic (antibody mediated). Conversely, the mouse platform was used to demonstrate that phagocytes, primarily macrophages, responded to infection through fungal ingestion (Young, 1958) and that pathogenicity of C. albicans could be enhanced by decreasing host defenses, e.g., through X-irradiation, identifying the role of phagocytic leukocytes (Roth et al., 1957; Gordee and Simpson, 1967).

An elegant approach by Miyake et al. (1977), using “nude” (congenitally athymic) mouse, demonstrated that nonimmune phagocytosis by macrophages were operational early after intravenous infection, while T cell–mediated immunity contributed to responses in later stages (Miyake et al., 1977). This distinction of innate response (this time, by neutrophils) from the acquired resistance phase (by T cells) was supported by others (Giger et al., 1978). Neutrophils were later assigned a more central role in innate resistance to candidiasis due to their increased fungicidal activity (compared with the conditionally fungistatic activity seen with macrophages) (Hurtrel et al., 1980; Kagaya and Fukazawa, 1981; Cutler and Poor, 1981). Meanwhile, in mice sensitized to C. albicans through previous infection (systemic or cutaneous), yeast-specific T cell responses detected either in vitro or in vivo (delayed hypersensitivity) became an established method to detect cellular immune responses (Domer and Moser, 1978; Moser et al., 1980). The study of murine lung macrophages revealed that these cells recognized zymosan and Candida comparably through a common glycoprotein-binding receptor that was opsonin independent and permitted phagocytosis; this putative mannose/glucosamine receptor pioneered the subsequent discovery of fungal pattern recognition receptors (Warr, 1980). Mouse peritoneal macrophages used an “oxidative burst,” similar to that defined in neutrophils, for killing phagocytosed Candida; moreover, differential fungal-killing activity may be candidal species dependent (Sasada and Johnston, 1980). Interestingly, macrophage candidacidal activity could be enhanced by extracts from L-929 fibroblasts (an murine cell line that secretes a macrophage colony–stimulating factor that activates bone marrow–derived macrophages) or from muramyl dipeptide (a bacterial cell wall component that stimulates production of various cytokines, including GM-CSF) (Prescott et al., 2020; Nozawa et al., 1980; Cummings et al., 1980), implying that host antifungal responses may be therapeutically tractable. Establishing these pillars of immune response to C. albicans (i.e., myeloid cells mediate innate resistance; T cells mediate acquired resistance) revealed that previous conflicting mouse results were partly due to intrinsic differences in strains used; in other words, genetic differences in immunological responses accounted for distinct murine susceptibility profiles to candidiasis.

Further insight into the molecular constituents of immune responses to Candida occurred with the identification of dectin-1 as an innate recognition receptor for β-1,3-d-glucan (a polysaccharide in most fungal cell walls) (Brown and Gordon, 2001). Murine macrophage activation of cell surface–expressed dectin-1 by fungal β-1,3-d-glucan triggers a pro-inflammatory, TNF-based response (Brown et al., 2003). While dectin-1 recognizes C. albicans yeast cells (Gantner et al., 2005), it cannot bind to its hyphae; the latter occurs with dectin-2, a separate receptor that recognizes high-mannose structures (Man[9]GlcNAc[2]) (McGreal et al., 2006; Sato et al., 2006). These distinct cognate interactions are fit for the polymorphic nature of C. albicans, which expresses different surface moieties when transitioning between yeast, pseudophyphal, and hyphal forms. Dectin-1 engagement mobilizes a canonical pathway, involving a Syk and a Card9/Bcl10/Malt1 complex that activates NFκB for cytokine production and antifungal responses (Gross et al., 2006). In dendritic cells (DCs), dectin-1 stimulation also activates phospholipase C (PLC)-γ, particularly PLCγ2, for intracellular Ca⁺² flux and secretion of various cytokines (Xu et al., 2009). To understand the bridge between myeloid–T cell responses established above, the Schwarzenberger lab found that IL-17 is crucial in a murine systemic/intravenous candidiasis study (Huang et al., 2004). This line of investigation culminated in the discovery that signaling through dectin-1–Syk–Card9 generates a CD4⁺ IL-17–producing effector T cell (Th17) response (LeibundGut-Landmann et al., 2007). Thus, the mouse platform was instrumental in identifying this key pathway for host resistance to candidiasis.

The mouse platform was initially used to study Aspergillus-derived toxins, as mycotoxicosis was a potentially fatal complication of spoiled foods. Aspergillosis complicating antibiotic- or cortisone/ACTH-based treatment of diseases, particularly malignancies, prompted laboratory animal investigations to study this mycosis. Human aspergillosis was observed primarily as a pulmonary disease, acquired through inhalation of spores. Thus, although various experimental methods of fungal inoculation were used, respiratory delivery of aspergilli conidia provided more physiological relevance for understanding host responses. While conventional laboratory mice exposed to aerosolized Aspergillus are resistant to lethal infection, fatal aspergillosis developed in cortisone-treated mice (Sidransky and Friedman, 1959; Sidransky et al., 1965); this was due to steroid-induced impairment of lysosome fusion to phagocytosed fungi within alveolar macrophages, enabling filamentous growth (Merkow et al., 1968). In a series of elegant experiments, combining in vitro studies (on cells from mouse and human) with in vivo approaches (intravenous infection to characterize inflammatory responses complemented with inhaled infection as a “realistic model of human disease”), Schaffner, Douglas, and Braude definitively demonstrated that monocytes/macrophages are the first line of defense against inhaled aspergilli spores (Schaffner et al., 1982, 1983). When fungal germination overwhelms them, recruited neutrophils become the major defense against mycelia. Compromise of both defenses, through either large doses of steroids or combined immunosuppression (one dose of steroids plus nitrogen mustard-induced myelosuppression) allows for fatal or disseminated aspergillosis. This framework not only explained the increasingly prevalent aspergillosis associated with exogenous immunosuppression but also the aspergillosis of patients with chronic granulomatous disease (CGD; due to defective oxidative killing activity in both neutrophils and monocytes) (Greenberg et al., 1977). Equally important, their work showed that alveolar macrophage-mediated immunity to aspergilli spores is independent of T lymphocytes or humoral responses. Indeed, the increased susceptibility to aspergillosis in humans with CGD, without exogenous immunosuppression, and the subsequent development of a mouse model of X-linked CGD (Pollock et al., 1995) provided the foundation for understanding the myeloid molecular mechanisms of human immunity to Aspergillus.

Thermally dimorphic fungi (TDF) grow as molds in their saprophytic (environmental) phase, but as yeast form at the elevated temperatures of their host. The more common genera include Blastomyces, Histoplasma, Coccidioides, Paracoccidioides, and Talaromyces (previously Penicillium) marneffei, with newer genera recently identified.

The clinical observations that histoplasmosis and coccidiodomycosis had similarities to tuberculosis (infected human lungs were characterized by fungi-harboring granulomata) (Macneal and Taylor, 1914; Beadenkopf and Loosli, 1951; Binford, 1955) and that human diseases of the reticuloendothelial system were associated with these mycoses (Zimmerman and Rappaport, 1954; Collins et al., 1951) pointed to macrophages as central to defense against TDF. This deduction was confirmed in ex vivo human experiments (Beaman and Holmberg, 1980; Newman et al., 1990; Brummer and Stevens, 1982) and in the mouse (Hill and Marcus, 1960; Miya and Marcus, 1961; Wu and Marcus, 1963; Howard, 1973). Research into the inconsistent in vitro behavior of murine macrophages in controlling fungal infections revealed that activation of macrophages through interaction with fungal antigen-specific T lymphocytes was required (Howard et al., 1971; Deepe et al., 1986). The mouse platform identified IFN-γ as essential for “macrophage activation” to control these fungi (Deepe et al., 1986; Beaman, 1987; Levitz and DiBenedetto, 1988). Further, T cell–derived IL-12 was crucial for induction of IFN-γ (Zhou et al., 1995). Since TDF yeasts were intrinsically resistant to neutrophil killing, this implied that intra-macrophagic antifungal activity was likely by non-oxidative (“respiratory burst”)–mediated killing (Schaffner et al., 1986). Further support for the importance of macrophage activation was the discovery of TNF production in response to these fungi, stimulating macrophages in a T cell–independent (autologous) manner (Smith et al., 1990; Wu-Hsieh et al., 1992). That some fungi had morphologic forms inherently resistant to neutrophil killing was postulated as the basis distinguishing opportunistic fungi (causing serious infections only in individuals with compromised host defenses, e.g., Candida and Aspergillus) from pathogenic ones (causing severe/progressive infections in otherwise healthy individuals, e.g., TDF) (Schaffner et al., 1986).

The same clinical reasoning for TDF also suggested that macrophages were important for host defenses to Cryptococcus neoformans (and related cryptococcal yeasts) (Mitchell and Friedman, 1972), confirmed in ex vivo human studies and in the rodent (Gentry and Remington, 1971; Mitchell and Friedman, 1972; Diamond and Bennett, 1973; Sethi, 1974). Macrophage phagocytosis could be enhanced by GM-CSF and TNF (Collins and Bancroft, 1992), while intracellular fungal control was activated through IFN-γ or M-CSF (Flesch et al., 1989; Mody et al., 1991; Brummer and Stevens, 1994). The antifungal activity was a CD4⁺ T cell–dependent process (Mody et al., 1990). Thus, despite mycological evolutionary divergence, TDF and cryptococci share immunological convergence in terms of required host defenses.

Because laboratory animals are not inherently susceptible to human fungal pathogens, it can be difficult to discern whether experimental findings represent “immune responses” (the spectrum of reactions elicited by fungal stimulation), “immunity” (host biology vital for resistance to infection or protection from disease), or even “immunopathology” (dysregulated immune reactivity causing organ damage, contributing to disease). The experimental studies mentioned were among the fundamental discoveries of antifungal immunology, but deciphering their exact roles in human immunity requires a complementary approach.

Defining immunobiological pathways indispensable for controlling infectious diseases in humans identifies those that are therapeutically targetable. This translational gap highlights the need to study patients naturally susceptible to fungal infections. The real-world setting is important: Most human fungal syndromes are nearly exclusive to humans, reflecting human-specific immunological responses. Whereas animal platforms frequently use large inocula, the fungal doses required to cause the various human mycoses are frequently unknown. Moreover, the experimental approach typically introduces fungi artificially, bypassing tissues now viewed as immunological, resulting in an abbreviated view of pathogenesis. As animals in experimental studies are typically isogenic or congenic, a common strategy is to study the impact when gene functions are lost. However, the molecular genetics underlying human susceptibility to infections are more complex: A gene with a loss-of-function (LOF) mutant allele can be asymptomatic if the other allele is wild-type (carrier) or disease-causing if paired with another mutant allele (autosomal recessive, AR) or with no allele (X-linked in males), or autosomal-dominant (AD) disease-causing if the mutant protein interferes with the wild-type protein (negative dominance), or if the remaining wild-type allele produces insufficient product to maintain normal processes (haploinsufficiency). LOF mutations can be partial or complete. A gain-of-function (GOF) mutation may enhance molecular responses (e.g., STAT1 GOF causes its prolonged phosphorylation [van de Veerdonk et al., 2011; Sampaio et al., 2013; Mizoguchi et al., 2014]) but disrupts homeostasis and cellular function (Boisson et al., 2015), or it may acquire new properties. Mutations in a given gene may potentially cause a range of distinct disorders, depending on which of these specific molecular impacts that mutation causes; this has been strikingly evident for a growing number of human immunity genes. Thus, using human models offers the opportunity to define disease-relevant defects linked to fungal susceptibility in real-world conditions and can even provide the initial insights into immunity pathways that would not otherwise be suspected.

Studies using human models of antifungal immunity in natura can be through the evaluation of clinically penetrant, rare genetic mutations (“inborn errors of immunity,” [IEI] or “primary immunodeficiencies”), their phenocopies (e.g., autoantibodies [aabs]), or conditionally penetrant variants (i.e., exerting their effects only in the presence of specific pathogens or environmental factors). One potential challenge with human models is attributing detectable abnormal immune responses as the cause of fungal susceptibility when they may actually be consequences of the fungal disease, or they are functionally redundant or simply epiphenomenon. The genetic approach is therefore appealing because it often provides more conclusive directionality: a faulty gene causes a defective immune response. More broadly, to correctly ascribe an experimentally identified “loss of immune function” as the underlying cause for the patient’s fungal disease, a fungal-susceptibility causation framework is proposed, structured along Koch’s postulates (Table 2). With this approach, the fundamental findings in the mouse can be mapped to human immunity pathways.

Before Berkhout’s taxonomic classification of Candida in 1923 (Berkhout, 1923), there was significant confusion in reported yeast species causing human disease; her work enabled microbiological certainty in clinical diagnoses. Candida, especially C. albicans, was then recognized to cause a superficial disease (i.e., affecting skin and mucous membranes), either as an acute, typically self-resolving infection or as chronic candidiasis (also then called “moniliasis”), with a prolonged course and refractoriness to therapy. Why some patients developed this chronic infection was poorly understood until associations with endocrine disorders were reported, including familial clusters (Esselborn et al., 1956). In 1967, Wuepper and Fudenberg studied a young man with long-standing moniliasis who subsequently developed adrenal and parathyroid insufficiency, identifying self-directed, organ-specific antibodies (Wuepper and Fudenberg, 1967). Strikingly, 17 of 28 studied family members also had aabs (moniliasis was not reported), prompting the hypothesis of a genetic basis for this syndrome which, in retrospect, was likely autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED). Further insight into susceptibility to chronic mucocutaneous candidiasis (CMC) was suggested by its invariable occurrence in patients with hereditary thymic alymphoplasia with lymphocytic hypoplasia and congenital agammaglobulinemia, a condition predictably fatal in infancy (Gitlin and Craig, 1963). Similarly, chronic oral moniliasis was seen at autopsy of three infants with congenitally absent thymus and parathyroid glands by DiGeorge (Kirkpatrick and DiGeorge, 1968). These conditions, now called SCID, implied the importance of T cells in mitigating CMC. Buckley and colleagues reported recurring oral moniliasis in a syndrome marked by repetitive abscesses, coarse facies, dermatitis, and elevated IgE levels (hyper-immunoglobulin E syndrome, HIES) (Buckley et al., 1968). These reports provided the IEI framework (APECED, SCID, and Job’s/AD-HIES) to study why CMC developed. The frequency of CMC in advanced HIV further supported the role of T cells. The common mechanism underlying susceptibility to CMC across these seemingly disparate disorders emerged when IL-17 was shown to be critical in the mouse immune response to Candida (albeit in the context of IC [Huang et al., 2004]), with the initial source of IL-17 being specialized Th17 cells (Langrish et al., 2005; LeibundGut-Landmann et al., 2007). This anchor was the foundation for in-depth, genetically driven studies of humans with CMC across diverse clinical conditions: It led to the discovery of numerous monogenic disorders marked by molecular defects in the production of, or in the response to, the IL-17 family of cytokines in patients with CMC through the inability to generate either functional T cells (e.g., SCID/CID) (Keles et al., 2016; Wang et al., 2016; Tangye et al., 2017; El Hawary et al., 2021; Fallahi et al., 2022), Th17 (e.g., AD STAT3, AD STAT1, AR IL12RB1, AR IL12B, AR RORC, and AR ZNF341) (Milner et al., 2008; Renner et al., 2008; Ma et al., 2008; van de Veerdonk et al., 2011; Liu et al., 2011; Smeekens et al., 2011; Toubiana et al., 2016; Hiller et al., 2018; de Beaucoudrey et al., 2008, 2010; Hatipoglu et al., 2017; Sarrafzadeh et al., 2019; Prando et al., 2013; Okada et al., 2015; Béziat et al., 2018; Frey-Jakobs et al., 2018; Frede et al., 2021), IL-17 (AD IL17F), or a functional IL-17–receptor complex (AR IL17RA, AR IL17RC, AR TRAF3IP2, encoding ACT1, and AD JNK1) (Puel et al., 2011; Fellmann et al., 2016; Lévy et al., 2016; Ling et al., 2015; Boisson et al., 2013; Bhattad et al., 2019; Shafer et al., 2021; Marujo et al., 2021; Li et al., 2019; Noma et al., 2023) (Fig. 2).

Because CMC occurs at the epithelium, some epithelial barrier defects may predispose to superficial candidal disease. Keratitis, ichthyosis, and deafness (KID) syndrome, due to genetically defective keratinocyte biology, increases susceptibility to CMC (Harms et al., 1984; Vinh, 2023). It is unclear if there is a mechanistic link between KID syndrome and IEIs with defective IL-17 immunity, although a paucity of Langerhans cells in the former has been reported (Rerknimitr et al., 2016). Beyond Th17 cells, other cells are implicated in the “type-17 response,” at least in the mouse platform (e.g., tissue-residing γδ-T cells, invariant NK-T cells, and innate lymphoid cells type 3) (Conti and Gaffen, 2015; Conti et al., 2016; Gaffen and Moutsopoulos, 2020). This opens the opportunity to identify further cellular and genetic defects underlying CMC in humans, including potential anomalies in mucosal-specific populations not found in the circulation. Intriguingly, in a subset of APECED patients with AIRE deficiency, mucosal type-17 responses were intact, with dysregulated IFN-γ locally driving the immunopathology of mucosal candidiasis (Aichele et al., 2006; Oikonomou et al., 2024). Thus, susceptibility to CMC appears to result from defective type-17 immunity, altered epithelial biology, and/or dysregulated immunopathological responses to fungal invasion.

In distinction to superficial disease, humans can also develop IC. These two syndromes (CMC versus IC) have often been considered mutually exclusive, owing to differences in “defense factors” (Schaffner et al., 1986). While acute iatrogenic IC is clinically familiar, there are sporadic reports of chronic central nervous system (CNS) infection with microbiologically confirmed Candida occurring without any preceding medical intervention or immunosuppression. This enigmatic syndrome has been occasionally called “monilial meningitis” or what we termed, spontaneous CNS candidiasis (Gavino et al., 2014). Based on murine research identifying CARD9 as crucial for host defense against Candida (Gross et al., 2006; LeibundGut-Landmann et al., 2007), AR CARD9 mutations were first reported in humans in 2009 (Glocker et al., 2009), and spontaneous CNS candidiasis was a defining manifestation (Gavino et al., 2014). Fascinatingly, CARD9 deficiency was found to cause another historically reported enigmatic human mycosis, “deep dermatophytosis,” or “tinea profunda” (Lanternier et al., 2013; Grumach et al., 2015; Zhang et al., 2019; Nazarian et al., 2020). Dermatophytes are keratinophilic fungi typically restricted to cutaneous infections, where keratin-producing cells lie. That loss of CARD9 permits these fungi to disseminate from nutrient-rich skin into lymphatics and viscera underscores the gatekeeping function of this molecule. CARD9 mutations predisposing to IFD are found globally, including in French-Canadians, Asians (e.g., Japan, Korea, and China), and African patients, some of which are recurring and established by founder effects (Gavino et al., 2016; Lanternier et al., 2013; De Bruyne et al., 2018; Tomomasa et al., 2024). Increased availability of genomic sequencing has uncovered CARD9 mutations in patients with other unexplained fungal diseases, particularly molds (e.g., hyalohyphomycetes, phaeohyphomyces, and mucormycetes) (Lanternier et al., 2015; Wang et al., 2018; Wang et al., 2019a; Perez et al., 2020; Erman et al., 2020; Imanaka et al., 2021; Wang et al., 2019b; Rieber et al., 2016). Although the dectin-1–Syk–CARD9/BCL10/MALT1 canonical pathway was deduced in the mouse, it is interesting that absent dectin-1 expression in humans is not rare (e.g., via the Y238X premature stop codon, which has minor allele frequencies ranging from 0.05% to 9.6% in populational databases) (Holland and Vinh, 2009; UCSC Genome Browser, 2025); loss of dectin-1 expression thus appears to be frequent but may only sporadically be associated with susceptibility to unusual fungi (Drummond et al., 2022) or partially contribute to increased risk of some fungal diseases in the hematopoietic transplant setting (Plantinga et al., 2009; Cunha et al., 2010; Chai et al., 2011; Kalkanci et al., 2020). Moreover, human genetic disorders of BCL10 (Torres et al., 2014; Van Den Rym et al., 2020; Garcia-Solis et al., 2021; Al-Tamemi et al., 2022; Alsaidalani et al., 2023) or MALT1 (Jabara et al., 2013; Punwani et al., 2015; Rozmus et al., 2016; McKinnon et al., 2014; Charbit-Henrion et al., 2017; Frizinsky et al., 2019; Sonoda et al., 2021; El Hawary et al., 2021) compromise immunity but do not increase the risk of IC (even though CMC is frequent in MALT1 deficiency linked to impaired induction of Th17 [Lu and Turvey, 2021]). Specific CARD9 mutations may affect signaling of other pathways, particularly in macrophages, and may benefit from GM-CSF therapy adjunctive to surgical resection and antifungals (Gavino et al., 2014, 2016). The precise mechanisms by which CARD9 increases susceptibility to IFD is actively being investigated.

Although invasive aspergillosis (IA) is a dreaded, treatment-associated infection, its occurrence in the absence of iatrogenesis was reported among a series of male children with “fatal granulomatous disease of childhood” in the 1950s (Good et al., 1968); this is now recognized as CGD due to genetic defects of the phagocyte NADPH oxidase (phox) complex, which impair the myeloid respiratory burst (Baehner and Karnovsky, 1968). Classic CGD, due primarily to X-linked mutations in CYBB (encoding the gp91^phox subunit of phox), but also to AR mutations in CYBA (p22 ^phox), NCF1 (p47 ^phox), NCF3 (p67 ^phox), or CYBC1 (EROS), yields neutrophils with profoundly impaired production of ROS to a broad array of agonists in vitro; in contrast, in atypical CGD (e.g., due to mutations in NCF4 (p40 ^phox) [van de Geer et al., 2018]), stimulated ROS production may be normal or decreased, but not abolished (Staudacher and von Bernuth, 2024). That 25–35% of patients with classic CGD develop IA, typically by Aspergillus fumigatus within the first two decades of life in otherwise normal lung parenchyma, while atypical CGD does not have this susceptibility (van de Geer et al., 2018), underscores the importance of the phox complex and ROS in human defenses against aspergilli (Vinh et al., 2010b) (Fig. 3). Intriguingly, CGD patients are also susceptible to Aspergillus nidulans complex, molds that ultra rarely infect other immunocompromised populations (Segal et al., 1998; Bhattarai et al., 2024). Through the study of mouse and human, we showed that the fungal cell wall content of galactosaminogalactan (GAG) confers resistance to neutrophil extracellular trap (NET)-mediated killing (NETosis) of aspergilli (Lee et al., 2015). A. fumigatus possesses abundant GAG, making it resistant to this process; A. nidulans has significantly lower GAG levels, rendering it highly susceptible (hence, its low virulence). With loss of NETosis (seen in classic CGD), A. nidulans is licensed to be pathogenic. Paralleling these genetic syndromes, corticosteroids in non-IEI settings are a significant risk factor IA (White, 2004), and these drugs inhibit the phox complex, reducing the ability to generate ROS (Umeki and Soejima, 1990; Welch and Devlin, 1983; Coates et al., 1983).

While these conditions underscore the phox complex and ROS as critical for human defenses to aspergilli, the precise immunological interplay by which this occurs is less clear. For example, we first noted IA occurs in AD-HIES (from dominant-negative STAT3 mutations) as a complication of lung cysts (pneumatoceles), in the absence of a myeloid defect in fungal killing (Vinh et al., 2010b) (Fig. 3). STAT3 regulates epithelial repair following injury, and since this is defective in AD-HIES, the pneumatocele may simply provide a niche for inhaled aspergilli to colonize for subsequent indolent invasion. This phenomenon would mirror IA in chronic obstructive pulmonary disease (Hammond et al., 2020). However, STAT3 is also activated by ROS in the respiratory epithelium to induce proinflammatory gene expression (Meganathan et al., 2022). Thus, the study of individuals with STAT3 mutations of distinct molecular mechanisms that compromise human immunity (via dominant-negative, haploinsufficiency or GOF) (Vinh, 2024) will define precisely how STAT3 protects against IA. Likewise, CARD9 deficiency has been reported with extrapulmonary (Rieber et al., 2016; Zhang et al., 2021) and pulmonary (Perez et al., 2020) aspergillosis, and determining the interplay with the above molecules (if any) could provide significant clarity.

As discussed above, TDF and the yeast species of Cryptococcus (C. neoformans and Cryptococcus gattii complexes) are able to establish themselves within macrophages. Macrophage activation through IFN-γ from T cells is critical for control. The emergence of HIV, where these fungi are notoriously opportunistic (Minamoto and Armstrong, 1988; Grant and Armstrong, 1988), confirmed the necessity of T cells. This macrophage–IFN-γ–T cell framework is identical to that deduced for mycobacteria. The first humans with disseminated mycobacterial disease bearing null mutations in the IFN-γ-receptor (Jouanguy et al., 1996; Pierre-Audigier et al., 1997) (expressed on macrophages) or the IL12R (Altare et al., 1998) (expressed on NK or T cells to propagate the IFN-γ response) were seminal, proving that such phenomena generated in the mouse naturally occur in humans and cause a selective vulnerability. The first report of mutations in these molecules with fungal susceptibility was in 2005 for Paracoccidioides brasiliensis (Moraes-Vasconcelos et al., 2005) and Histoplasma capsulatum (Zerbe and Holland, 2005). Subsequently, mutations in genes encoding molecules downstream of the IFN-γ-receptor or the IL12R, as well as genes that impair the production of monocytes/macrophages, of T cells, or of their CD40-ligand (CD40L)-mediated costimulation, have been found in patients with TDF (Fig. 4) (Vinh et al., 2009, 2010a, 2011; Hsu et al., 2011; Sampaio et al., 2013; Lee et al., 2014, 2019; Liu et al., 2022; Xing et al., 2024; Schimke et al., 2017; Spinner et al., 2016; Du et al., 2019; Peñafiel Vicuña et al., 2023). Genetic defects in this pathway were also found in patients with unexplained cryptococcosis (Dotta et al., 2016; Marinelli et al., 2020; Jirapongsananuruk et al., 2012). The molecular effects from LOF and GOF mutations described above are particularly evident in the genetic lesions of this axis. These findings emphasize that in patients with unexplained disease with these fungi, pursuit of a genetic etiology can be informative. Equally important to consider is that, while fungi are often categorized as “ubiquitous,” TDF/cryptococci are not omnipresent globally but are concentrated in distinct (albeit enlarging) geographic regions. Genetic mutations conferring susceptibility specifically to them may be silent in areas where these fungi are not prevalent and manifest only upon migration to more endemic areas. Notably, infections due to certain genetic lesions of the macrophage–IFN-γ–T cell pathway may be treatable with adjunctive IFN-γ (Vinh et al., 2011; Casanova et al., 2024).

While defects in this axis helps understand risk for disseminated disease, they are rarely found in those with disease confined to the lungs, and the immunologic basis distinguishing acute versus chronic-progressive pulmonary disease from these fungi is not well understood. Perhaps this simply reflects selection bias of cases undergoing further investigations. Alternatively, it suggests that infections at portals of entry (e.g., lung, gut, and skin) are controlled by tissue-specific immune responses, which may not be identifiable through the functional study of circulating immune cells; animal platforms focused on these tissue responses and patient-derived organoids may be informative here. Moreover, the TDF are notoriously associated with distinct syndromes, some of which are rare; because they are (to our current knowledge) only seen in humans, the mouse platform may not provide accurate insight into their pathophysiology. For example, the idiosyncratic bases for histoplasmosis-associated fibrosing mediastinitis, or the reactive rashes (erythema multiforme; erythema nodosum) associated with pulmonary coccidioidomycosis, remain obscure. These sequelae do not seem to result from ongoing infection, and antifungal therapy alone provides little to no benefit. Studying humans with these immune-mediated complications is the avenue most likely to help understand their biological mechanisms.

Pneumocystis was first identified by Chagas in 1909 in guinea pigs (Chagas, 1909; Gajdusek, 1976). 2 years later, it was found in the lungs of a severely debilitated adult who died from American trypanosomiasis (Gajdusek, 1976). Half a century after, it was linked to numerous outbreaks of interstitial plasma cell pneumonia in prematurely or malnourished infants in Europe (Gajdusek, 1957). In the 1960s, it was recognized as an opportunistic infection in patients with lymphoreticular malignancies and those receiving organ transplants. Sporadic fatal cases in otherwise healthy adults, confirmed by autopsy, were also reported, including instances of alveolar proteinosis on histopathology (Nagai, 1965). In the 1970s, Buckley’s immunologic evaluations of infants with Pneumocystis jirovecii pneumonia (PCP), without hematologic malignancy, identified it among those who had SCID, X-linked hyper-IgM (due to CD40-ligand deficiency), Nezelof syndrome (T cell immunodeficiency from thymus atrophy), and Wiskott–Aldrich syndrome, thus demonstrating that “thymus-dependent immunity” (T cells) were important in defending against Pneumocystis (Whisnant and Buckley, 1976). In the mid-1980s, this finding was underscored by the emergence of PCP in previously healthy males as the sentinel event marking the HIV pandemic (Centers for Disease Control, 1981a, 1981b; Gottlieb et al., 1981).

Human diseases continue to define immunity to P. jirovecii. Disorders affecting mucociliary clearance (cystic fibrosis; primary ciliary dyskinesia) are not prone to PCP, suggesting this function is redundant in pneumocystis host defense. Within the lung parenchyma, the ability to generate or maintain functional T cells is central, as seen by the growing number of T cell–deficient IEIs that develop PCP or the increased risk seen with steroids. Whereas IEIs with mutations in T cell–costimulatory pathways of CD28 (Wang et al., 2016; Béziat et al., 2021; Lévy et al., 2023) or ICOS (Abolhassani et al., 2020; Chou et al., 2015)/ICOSL (Roussel et al., 2018; Loo et al., 2022) are surprisingly not predisposed to PCP, mutations in the signaling axis of CD40L (on T cells)–CD40 (on APCs) are (Gennery et al., 2004; Danielian et al., 2007; Cabral-Marques et al., 2012; Du et al., 2019; Al-Saud et al., 2013; Banday et al., 2023). The exact APCs involved is less clear. Syndromes of monocytopenia or DC deficiencies (e.g., GATA2 and IRF8) rarely develop PCP (Vinh et al., 2010a; Spinner et al., 2014; H ambleton et al., 2011; Bigley et al., 2018; Mace et al., 2017), except one case with concomitant lymphopenia (González-Lara et al., 2017). In GATA2 deficiency, persistence of tissue macrophages (potentially with residual APC function), despite monocytopenia, may explain this (Vinh et al., 2010a). PCP complicated by alveolar proteinosis also implies a role for alveolar macrophages. In mouse studies, DC or B cells can function as lung APC for Pneumocystis to T cells, using CD40⁻CD40L signaling (Wiley and Harmsen, 1995). Murine B cells also confer protection against reinfection and resolve inflammation following Pneumocystis clearance (Noell et al., 2022; Kolls, 2017). Interestingly, adults undergoing B cell depletion with therapeutic mAb are at significantly higher risk of PCP than what is expected from congenital disorders of B cell production (e.g., X-linked agammaglobulinemia) (Zalmanovich et al., 2020; Ghembaza et al., 2020; Park et al., 2022). The reasons for this risk are likely multifactorial: immunosuppression preceding/concomitant with B cell depletion contributes, but it may also signify redundancy in APC function between DC and B cells in infancy, where DC can compensate for the congenital absence of B cells, but not for their sudden depletion in adulthood. Further studies will refine our molecular understanding of P. jirovecii defenses.

The concept that antibodies targeting immune molecules predispose to infectious diseases is not new: With increasing use of mAb for various conditions, this type of iatrogenic immunosuppression is well recognized. The previous use of cytokines as therapy (e.g., IFN-α for hepatitis C [Bonino et al., 1997]) revealed that antidrug aabs could develop, which did not increase infection risk but hindered its treatment. Similarly, feto-maternal incompatibility with maternal isoimmunization may cause neonatal neutropenia (Lalezari et al., 1960, 1971). Aabs to self-target following a microbiologically documented infection may be directed to tissue molecules resulting in end-organ damage, while aabs to lymphocytes were found in some patients with advanced HIV (Dorsett et al., 1985; Stricker et al., 1987). In distinction to these exogenously induced cases, there is growing recognition that intrinsic, naturally occurring aabs to immunological molecules increase infection susceptibility. Aabs to neutrophils outside the neonatal period, causing chronic neutropenia with pyogenic infections, was among the first phenomena observed (Boxer et al., 1975; Lalezari et al., 1975). Aabs to the neutrophil antimicrobial peptide, bactericidal permeability-increasing protein, were identified in patients with cystic fibrosis, associated with poorer pulmonary function, and interfered with neutrophil-mediated killing of Pseudomonas aeruginosa, possibly contributing to chronic infection with mucoid strains of this bacteria (Zhao et al., 1996; Aichele et al., 2006). Aabs to IFN-γ underlying disseminated mycobacterial disease was first reported in 2004 (Döffinger et al., 2004; Höflich et al., 2004). Aabs to other cytokines (in the brackets that follow) have been found in various other conditions, including autoimmune pulmonary alveolar proteinosis (aPAP; GM-CSF) (Kitamura et al., 1999), neutropenia in Felty’s syndrome (G-CSF) (Hellmich et al., 2002), recurrent staphylococcal skin and soft tissue infection (IL-6) (Puel et al., 2008), select viral infections (type I IFN) (Walter et al., 2015; Bastard et al., 2020, 2021), and severe EBV disease (IL-27) (Martin et al., 2024).

With respect to mycoses, aabs targeting IFN-γ have been identified primarily in talaromycosis (Tang et al., 2010; Wongkulab et al., 2013; Guo et al., 2020; Chen et al., 2021c), but also in cryptococcosis and histoplasmosis (van de Vosse et al., 2017; Chetchotisakd et al., 2007), consistent with the murine and human genetic studies that macrophage activation controls these pathogens. Patients harboring aab to IFN-γ have been predominantly middle-aged Southeast Asian women, who may also develop disseminated infection from Mycobacteria, Salmonella, or other intracellular bacteria (Shih et al., 2021). Further congruent with this immune framework, aabs to GM-CSF have been found primarily in patients with unexplained CNS cryptococcosis (mainly with C. gattii complex) (Saijo et al., 2014; Kwon-Chung and Saijo, 2015; Kuo et al., 2017; Applen Clancey et al., 2019; Stevenson et al., 2019; Perrineau et al., 2020; Viola et al., 2021; Yang et al., 2021; Goupil de Bouillé et al., 2022; Arango-Franco et al., 2023; Jiang et al., 2024). Although aab to GM-CSF may also cause aPAP, the opportunistic infections may precede or follow aPAP. In distinction, aabs targeting IL-17 and/or IL-22 have been found in CMC (Puel et al., 2010; Kisand et al., 2010). Because aabs can also be induced by infection, with most cases of aabs observed during chronic fungal diseases, and antibodies can be induced de novo within 10–14 days after the triggering event, a valid question is whether they are the cause or the consequence of the corresponding mycoses. Several arguments favor causality. First, in conditions like APECED and CMC, where germline mutations cause a loss of tolerance and aabs develop as a primary event, the aabs precede fungal disease (Puel et al., 2010; Kisand et al., 2010; Wolff et al., 2013; Sarkadi et al., 2014). Second, the high-titer, functionally neutralizing aabs identified (often blocking supraphysiologic concentrations in vitro) are linked to the same specific fungal diseases found in patients with rare genetic defects in the corresponding immunologic pathways, arguing against these aabs developing by chance. Additionally, the fungal diseases caused by these natural rogue aabs or their corresponding genetic lesions overlap with those complicating mAb therapy (e.g., anti-TNF and TDF or Cryptococcus [Wallis et al., 2004]; anti–IL-17 and CMC [Saunte et al., 2017]), although the latter is beyond the scope of this review. Altogether, these findings indicate that immunocompromising aabs can cause immunodeficiency and increase susceptibility to fungal diseases.

Efforts to understand how these aabs develop are underway. Potently neutralizing, high-titer aabs to IFN-γ, which have a Southeast Asian predominance, genetically associate with distinct HLA class II haplotypes (HLA-DRB1∗15:02/16:02; HLA-DQB1∗05:01/05:02) (Pithukpakorn et al., 2015; Ku et al., 2016; Chi et al., 2013). These aabs can recognize a major epitope at the C terminus of IFN-γ, which is not only crucial for its capacity to activate the IFN-γ receptor but also shares significant sequence homology with the ribosomal Noc2 protein of Aspergillus (Lin et al., 2016). Thus, “molecular mimicry” is postulated, whereby the Aspergillus Noc2 protein (or a cross-reactive environmental homolog), within the context of these Southeast Asian–specific HLA haplotypes, triggers the aberrant production of polyclonal neutralizing aabs to IFN-γ (Lin et al., 2016). However, neutralizing aabs to IFN-γ may target distinct IFN-γ epitopes without known homology to fungal proteins (Shih et al., 2022; Peel et al., 2024). Further, the prevalence of these HLA haplotypes in Southeast Asians (e.g., 2.6–18.8% [Ku et al., 2016]) is discordant with their frequency of IFD, while development of aabs to IFN-γ in individuals bearing these haplotypes is rare (Peel et al., 2024). Collectively, the findings suggest that these HLA haplotypes appear necessary but are not sufficient for the development of these pathologic aabs and that mechanisms beyond molecular mimicry to Noc2 may account for their development. Similarly, aPAP in Japanese patients was associated with an HLA class II haplotype (HLA-DRB1*08:03) that correlated with increased levels of aabs to GM-CSF (Sakaue et al., 2021). In Caucasian patients with aPAP, no HLA association has been found (Anderson et al., 2019), whereas aPAP in West Chinese patients associates with a different HLA class II haplotype (HLA-DRB1*14:54) (Li et al., 2023). Whether an epitope is necessary to trigger aab development in the different HLA contexts needs investigation, although endogenous GM-CSF itself may be driving the antibody response (Wang et al., 2013).

In distinction to individual cases of severe fungal disease caused by rare, sporadic, or familial penetrant gene defects or an aab phenocopy, ethnic-specific susceptibility to mycoses has long been recognized but only recently started to become decoded. Here, epidemiologic studies have identified fungal syndromes, either specific fungal diseases or disproportionately elevated rates of particular fungal manifestations, that are enriched in certain ancestry-based populations (Fig. 5). The hypothesis is that select fungi exploit an ethnic-specific variant with subtle impact on host defense. Notably, given that these persons are otherwise healthy, these immunogenetic defects do not confer susceptibility to a broad range of microbes.

One of the earliest-described ethno-enriched mycoses is tinea imbricata (also called “Tokelau ringworm”), a chronic dermatophytic infection caused by Trichophyton concentricum (Bonifaz and Vázquez-González, 2011; Anderson, 1880). The disease manifests typically in childhood with noninflammatory, concentric scaling rings on the torso and limbs that may become chronic, rendering the skin leathery or scaly, intensely pruritic, and prone to secondary bacterial infections. Tinea imbricata is overwhelmingly restricted to indigenous populations of Oceania (hence the original publications in Tokelau atolls and Papua New Guinea), Southeast Asia, as well as Central and South America (Er et al., 2022). A genetic basis was first postulated by Schofield et al. (1963). Subsequent geno-epidemiologic studies proposed a recessive inheritance to susceptibility, estimating the recessive-gene frequency at 31.5–48.9% (Serjeantson and Lawrence, 1977; Ravine et al., 1980). Although no gene/locus has been yet identified, this framework suggested that genetic susceptibility to a geographically limited fungus affecting a relatively large population may not be due to rare (e.g., <0.1%) variants, but rather, to more common ones established in that population, which the fungus leverages. It also implies a potential coevolutionary adaptation between humans and some fungi, akin to that seen with malaria (Carter and Mendis, 2002).

This ethno-enriched phenomenon has also been observed with blastomycosis. Epidemiologic studies in Manitoba and northwestern Ontario suggest a higher burden of blastomycosis among regional Indigenous populations, including increased incidence, earlier age of infection, and/or more severe disease (Crampton et al., 2002; Dalcin and Ahmed, 2015). Unfortunately, most research has focused on socio-economic factors (e.g., smoking or comorbidities [Dalcin and Ahmed, 2015]) affecting disease rate or outcome, rather than on ancestry-based biological susceptibility. Of course, the two are not mutually exclusive, but the immunologic basis for severe blastomycosis in these people remains unanswered. A similar observation of increased blastomycosis incidence was noted among the Hmong population of Wisconsin, relative to those of European ancestry, with respective rates of 168 versus 13 (per 100,000) (Roy et al., 2013). The Hmong, an East-Asian ethnic group, have remained largely endogamous. To better understand their susceptibility to blastomycosis, genomic studies with gene enrichment analysis identified variants at the IL6 locus, and cells from Hmong donors produced less IL-6, with decreased production of IL-17 by memory CD4⁺ T cells, compared with co-residents of European ancestry (Merkhofer et al., 2019). Additionally, the authors used a mouse model to confirm that loss of IL-6 and consequently IL-17–producing CD4⁺ T cells increases susceptibility to Blastomyces dermatitidis. The Hmong subjects did not have high rates of other infections, despite the fact that IEI with profound defects of IL-6-related pathways demonstrate such susceptibility (Béziat et al., 2020; Chen et al., 2021b).

Increased rates of disseminated, extrapulmonary coccidioidomycosis (DCM) have been observed among African-Americans (AA) (Ruddy et al., 2011; Hector et al., 2011; Vinh, 2011). Although isolated cases of DCM have been reported in patients with defects in the IFN-γ pathway or STAT3 haploinsufficiency (Powers et al., 2009; Vinh et al., 2011; Odio et al., 2015; Sampaio et al., 2013), the rarity of these latter deleterious alleles contrasts with the larger-scale frequency of DCM. Using whole-exome sequencing, Hsu et al. (2022) identified two additional DCM patients with STAT3 haploinsufficiency, strengthening the association between this IEI and DCM (Hsu et al., 2022). To identify additional susceptibility variants, the gene enrichment strategy identified variants in dual oxidase-1 (DUOX1) and dual oxidase maturation factor-1 (DUOXA1). DUOX1 is a NADPH oxidase (distinct from phox complex, above) primarily involved in hydrogen peroxide production in epithelial cells; DUOXA1 supports proper apical plasma membrane localization and function of DUOX1. AA patients with DCM harbored a disproportionate rate of variants in DUOX1 (discovery cohort: 3/18) or DUOXA1 (7/18), relative to non-AA subjects and compared with their general population frequency in gnomAD. These variants in DUOX1/DUOXA1 were found in either isolated heterozygosity (n = 5), with two variants (n = 1), or co-occurring with a variant in the fungal pattern-recognition receptor, dectin-1 (n = 3). In a validation cohort, AA with DCM carrying variants in DUOX1 (5/48) and DUOXA1 (6/48) were found. Collectively, DUOX1/DUOXA1 variants were found in 21/66 (32%). The biological relevance of the overrepresented DUOX1/DUOXA1 variants is supported by the finding of enriched variants in the upstream molecules, dectin-1 and PLCG2, although these latter two were primarily found in non-AA subjects. Despite these ancestral differences, the findings suggest a pathway that may contribute to DCM susceptibility, where coccidioidal endospore recognition involving dectin-1 triggers signaling via PLCG2, activating ROS from DUOX1/DUOXA1. The involvement of STAT3 in this pathway (based on STAT3 haploinsufficient patients) is undefined but is potentially through its effect on DUOX1/DUOXA1 expression (Gorissen et al., 2013). DUOX1 is important for lung epithelial regeneration (Gorissen et al., 2013), a process defective in AD-HIES/Job’s syndrome due to dominant-negative STAT3 mutations (Vinh et al., 2010b) and, interestingly, CNS coccidioidomycosis has been reported in such patients (Stanga and Dajud, 2008; Powers et al., 2009; Odio et al., 2015). It is noteworthy that IL-6 (identified in the Hmong with severe blastomycosis [Merkhofer et al., 2019]) is functionally related to STAT3, implicating a shared/overlapping host response pathway to these two TDF. Given the importance of macrophages in these mycoses, the relationship between these pathways and IFN-γ warrants exploration.

Equally interesting is why diminished function of these molecules (IL-6 and STAT3) at an ethno-demographic level associates primarily with these significant fungal diseases but not other infections, notably bacterial, as seen in IEI with severe defects in these molecules (Béziat et al., 2020; Chen et al., 2021b). This discrepancy may suggest an IL-6- or STAT3-driven signaling gradient that leads to a spectrum of immune responses, each differentially required by specific host cells to combat different pathogens. Consequently, genetic variants that weaken selective immune responses lower them below the protective threshold required for specific pathogens (but not to other microbes), allowing a specific infectious disease phenotype to develop. Interestingly, the IL6 variants connected to severe blastomycosis also associate with protection against severe COVID-19 (Chen et al., 2021a), highlighting that the detrimental/beneficial effects of these enriched variants are context dependent.

Perhaps not all ethno-enriched mycoses are monogenic in origin. Since the 1950s, studies identified that Indigenous Australians in the Northern Territory were disproportionately affected by a yeast (ultimately C. gattii) (Lo, 1976; Ellis, 1987). Pulmonary disease was common, but CNS involvement occurred frequently; most affected Indigenous individuals were not overtly immunocompromised (Lo, 1976; Ellis, 1987; Fisher et al., 1993; Jenney et al., 2004). The predilection for these peoples was striking: one study showed rates of 10.4 (vs 0.7) per million persons (Chen et al., 2000); another estimated a relative risk of 20.6 compared with non-Indigenous people (Fisher et al., 1993). While initial hypotheses attributed this high prevalence to eucalyptus tree exposure (Ellis and Pfeiffer, 1990), infections later occurred in non-Indigenous persons without such exposure (e.g., in Canada [Hoang et al., 2004; Kidd et al., 2004]). The prevailing paradigm then became that C. gattii preferentially infected “immunocompetent” people—typically meaning those without HIV/chemotherapy—though this misnomer (meant to describe “previously healthy persons”) hindered further inquiry. Ultimately, research for an underlying cause revealed that C. gattii infection could be the sentinel manifestation of Aabs to GM-CSF (Saijo et al., 2014; Yang et al., 2021); thus, affected individuals were not truly “immunocompetent.” Whether aabs to GM-CSF are enriched in the Aboriginal Australians and Torres Strait Islanders, causing their predisposition to cryptococcosis, remains to be shown. However, this association is biologically plausible, given the prevalence of aabs to IFN-γ in women of Southeast Asian descent (Hong et al., 2020). A distinct aab, or a genetic cause, may alternatively be responsible, underscoring the need for further investigations. It is worth noting that a unique mating event enabled the emergence of C. gattii (Fraser et al., 2005), highlighting the complex interplay between fungal evolution and host susceptibility factors.

Another example of an ethno-enriched mycosis is lobomycosis, a chronic, granulomatous skin and subcutaneous disease caused by the extremely fastidious fungus, Lacazia loboi. It is primarily confined to Latin America, notably prevalent among the Kaiabi Indians of Central Brazil, where it is called “piraip” (Lacas Cda, 1981; Florian et al., 2020) and the Amer-Indian communities of Columbia (e.g., Amoruas, Wipiwi, and Motilones) (Rodríguez-Toro and Tellez, 1992; Arenas et al., 2019). The biologic reasons for this restricted susceptibility are unknown.

These examples of ethno-enriched mycoses call for a re-evaluation of fungal diseases that are geographically restricted and disproportionately affect specific ethnic groups. Previous explanations for some of these mycoses have focused on socio-economic factors and lifestyle activities (e.g., walking barefoot; eucalyptus tree exposure), but arguably, this approach is overly simplistic. While fungal exposure/infection may be attributed to social behaviors, and optimal medical management constrained by socio-economic inequalities, susceptibility to disease warrants biological investigations. As illustrated above, such research may identify immunity pathways that are ethno-specific and amenable to targeted public health interventions, while also providing novel insights into host defense against pathophysiologically related fungi.

Human susceptibility to fungal syndromes in natura is shaped by the interplay of mycology, immunology, and genetics. While the latter two are critical to understand the host aspect of “host–pathogen interactions,” they may be perceived as esoteric or experimental with unclear medical relevance. The clinical contexts in this review emphasize their importance as essential, complementary tools. Defining the molecular determinants of resistance/susceptibility to fungal diseases not only enhances our understanding of extreme individual cases, it also increases our knowledge of high-risk demographics. These insights have broad applications, including use of adjunctive host-directed immunotherapy to treat fungal diseases, development of relevant biomarkers to objectively evaluate the “net state of immunosuppression,” or development of polygenic risk scores for preventative care. Ultimately, integrating these disciplines can help translate the malbolge of mycoses into coherent plans for improving outcomes.

D.C. Vinh is supported by the Fonds de la Recherche en Santé du Québec Senior clinician-scientist research scholar program. This work was supported by the Shawnea D. Roberts Project of the McGill University Health Center Foundation.

Author contributions: D.C. Vinh: conceptualization, formal analysis, funding acquisition, investigation, methodology, project administration, resources, supervision, validation, visualization, and writing—original draft, review, and editing.