Genetic variation and fungal infection risk: State of the art

Abstract

Purpose of review

Fungal infections cause significant mortality in patients with acquired immunodeficiencies including AIDS, hematological malignancies, transplantation, and receipt of corticosteroids, biologics or small-molecule kinase inhibitors that impair key immune pathways. The contribution of several such pathways in antifungal immunity has been uncovered by inherited immunodeficiencies featuring profound fungal susceptibility. Furthermore, the risk of fungal infection in patients with acquired immunodeficiencies may be modulated by single nucleotide polymorphisms (SNPs) in immune-related genes. This review outlines key features underlying human genetic fungal predisposition.

Recent findings

The discovery of monogenic disorders that cause fungal disease and the characterization of immune-related gene SNPs that may regulate fungal susceptibility have provided important insights into how genetic variation affects development and outcome of fungal infections in humans.

Summary

Recognition of individualized genetic fungal susceptibility traits in humans should help devise precision-medicine strategies for risk assessment, prognostication and treatment of patients with opportunistic fungal infections.

Introduction

Despite continuous and ubiquitous exposure of humans to fungal microorganisms via the respiratory and gastrointestinal mucosal surfaces and the skin, the majority of these fungal encounters do not result in clinical disease. Endothermy and homeothermy [1], and the induction of potent innate and adaptive antifungal immune responses account for the resistance of mammals against most fungi [2, 3]. In the past few decades, advances in clinical medicine that include the wider implementation of hematopoietic stem cell or solid organ transplantation and the advent of effective chemotherapeutic and/or immunomodulatory treatments for neoplastic and autoimmune diseases have led to a significant expansion of patient populations with iatrogenic immune suppression that are at risk for developing opportunistic fungal infections [2, 3].

Despite the administration of antifungal drugs with potent activity in vitro and in preclinical models, such fungal infections carry unacceptably high mortality rates and represent unmet medical conditions. To improve fungal infection-associated patient outcomes, research efforts have primarily focused on the discovery of novel effective antifungal agents and the development of improved fungal-targeted diagnostic tests [4, 5]. More recently, increased research interest has been generated in identifying individualized genetic factors that may enhance the risk of developing opportunistic fungal disease and/or suffering worse outcomes from such infections. Indeed, such knowledge could aid in devising precision medicine strategies for risk stratification, prognostication, prophylaxis, vaccination and/or treatment of patients at risk for opportunistic fungal infections.

The research field of immunogenetic risk of fungal disease in humans has been largely ignited by the discovery and study of inherited monogenic disorders that cause susceptibility to fungal infections, which has revealed important immunoregulatory pathways that are specialized for the tissue-specific control of fungal pathogens [6–8]. The characterization of these pathways has catalyzed the study and identification of SNPs in immune-related genes within the same or other signaling pathways that may regulate the risk of fungal disease in patients with acquired immunodeficiency states.

Herein, I briefly outline current concepts pertaining to genetic variation in immune pathways, whether monogenic or not, which regulate protective mucosal and systemic host defense against the most common human fungal pathogens such as Candida, Aspergillus, Cryptococcus, and endemic dimorphic fungi. This review discusses both a) inborn errors of immunity that underlie the spontaneous development of severe human fungal disease and b) immune-related gene SNPs that may modulate the risk of acquisition and/or outcome of fungal infections in critically-ill patients in the intensive care unit (ICU) and in patients with iatrogenic immunosuppression such as recipients of allogeneic hematopoietic stem cell transplantation (HSCT).

Inherited monogenic disorders that predispose to chronic mucocutaneous candidiasis (CMC): The key role of IL-17 receptor (IL-17R) signaling

In 2009, Sarah Gaffen’s laboratory was the first to demonstrate the critical contribution of IL-17R signaling in host defense against oropharyngeal candidiasis in mice [9–11]. Mechanistically, IL-17 cytokines (i.e., IL-17A, IL-17F) that are produced locally at the mucosa by αβ T cells (natural Th17 cells), by γδ T cells, and, to a lesser extent, by innate lymphoid cells type 3, act on IL-17RA and IL-17RC on the surface of mucosal epithelial cells to induce the generation of potent antimicrobial peptides (e.g., β-defensin 1, β-defensin 3, S100a8, S100a9) that exert direct anti-Candida activity and restrict mucosal fungal invasion [9–14]. Concordantly, in 2011, seminal work led by Jean-1Laurent Casanova and Anne Puel showed that genetic deficiency of IL-17R signaling in humans, in the form of either IL-17RA or IL-17F deficiencies, predisposes to CMC, which is characterized by recurrent infections of mucosal surfaces by Candida species [15]. Follow-up work by the same group discovered that inherited deficiencies in IL-17RC or the IL-17R adaptor ACT1 (TRAF3IP2) also drive susceptibility to CMC in humans [16–18]. Some of these monogenic disorders (i.e., IL-17RA and ACT1 deficiencies) can also manifest with staphylococcal skin disease and pulmonary bacterial infections, indicative of broader mucocutaneous host defense impairments caused by IL-17R signaling defects [15–18]. Notably, consistent with the segregation of immune factors that are required for mucosal versus systemic control of Candida [3, 19], the aforementioned inborn errors of IL-17R–mediated immunity do not predispose patients to systemic candidiasis despite the recurrent nature of CMC.

Additional inherited immunodeficiencies that are caused by mutations in other genes beyond the IL-17R signaling cascade manifest with CMC by directly or indirectly affecting IL-17R–dependent immune responses [8]. Such examples include (but are not limited to) RORC mutations that impair Th17 cell development [20], autosomal-dominant hyper-IgE (Job’s) syndrome caused by dominant-negative STAT3 mutations that abrogate STAT3-dependent RORγt-mediated generation of Th17 cells [21], DOCK8 and CARD9 deficiencies that lead to defective Th17 cell differentiation [22, 23], STAT1 gain-of-function mutations that impair Th17 cell development indirectly via the induction of Th17 cell-inhibitory cytokine circuits [24], and autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) caused by AIRE mutations that feature neutralizing autoantibodies against Th17 cell-derived cytokines [25, 26], similar to patients with thymoma [27], who also develop mucosal candidiasis (reviewed in detail elsewhere [3, 6–8]).

Of interest, the introduction of IL-17R signaling-targeted biologics in the treatment of inflammatory and autoimmune disorders, primarily psoriasis and inflammatory bowel disease, has provided an additional layer of clinical evidence for the crucial role of this immunoregulatory pathway in mucosal host defense against Candida in humans. Indeed, patients who receive biologics that inhibit IL-12p40 (ustekinumab), IL-23p19 (guselkumab, tildrakizumab), IL-17RA (brodalumab), IL-17A (secukinumab, ixekizumab) or IL-17A/IL-17F (bimekizumab) occasionally develop refractory mucocutaneous, but not systemic, candidiasis [28].

Inherited monogenic disorders that predispose to invasive fungal infections: Fungal infection-specific differential contribution of neutrophils, mononuclear phagocytes and T cells to effective host defense

The identification and characterization of a plethora of inherited monogenic disorders in recent years has highlighted the critical contribution of certain immunoregulatory pathways and immune cell subsets in host defense against invasive infections by Candida, Aspergillus, endemic dimorphic fungi, and Cryptococcus [7].

Invasive candidiasis

Effective immunity against invasive candidiasis depends on myeloid phagocyte recruitment and effector function [19, 29]. The role of oxidative burst-dependent phagocyte fungal killing in mediating control of invasive candidiasis has been long-recognized given that a proportion of patients with complete myeloperoxidase deficiency or chronic granulomatous disease (CGD), caused by mutations in the NADPH oxidase complex, can spontaneously develop invasive Candida infections without an associated breach in mucocutaneous barriers by central intravenous catheters, abdominal surgery or chemotherapy-induced mucositis [30, 31]. However, the majority of myeloperoxidase-deficient and CGD patients do not develop invasive candidiasis indicating that an intact mucocutaneous barrier, which as mentioned earlier depends on functional IL-17R signaling, and non-oxidative burst-dependent mechanisms of phagocyte fungal killing can compensate for the lack of reactive oxygen species-mediated phagocyte functions.

In recent years, CARD9 deficiency has emerged as an important inherited immunodeficiency that predisposes to both mucosal and invasive candidiasis, being the only monogenic disorder known to date to combine enhanced mucosal and systemic Candida infection risk [32–36]. Of interest, patients with CARD9 deficiency only develop fungal disease without infection susceptibility to non-fungal microorganisms or predisposition to non-infectious complications [22]. Importantly, CARD9-deficient individuals develop invasive Candida infections with a predilection for certain anatomical sites, namely the central nervous system (CNS), the eyes, the bone and the gut, without reported hepatosplenic or renal candidiasis thus far.

The CNS-targeted fungal susceptibility of CARD9-deficient patients has recently been elucidated. Specifically, CARD9 deficiency is associated with a significant defect in mobilizing neutrophils to the Candida-infected CNS tissue in mice and humans [32, 37]. This defect lies at the level of production of key mediators of neutrophil recruitment in the infected CNS tissue rather than at the level of neutrophil-intrinsic chemotaxis. Indeed, we recently showed that sequential production of IL-1β and CXCL1 by CARD9-expressing CNS-resident microglia, upon their stimulation by the Candida albicans secreted peptide toxin candidalysin [38, 39] and subsequent activation of p38 and c-Fos signaling, is fundamental for the trafficking of protective CXCR2-expressing neutrophils from the blood into the Candida-infected CNS [37]. This axis is impaired in CARD9 deficiency and results in CNS-specific neutropenia during fungal disease that contributes to the CNS infection susceptibility of CARD9-deficient patients. Moreover, the limited number of neutrophils that accumulate in the infected CNS are defective in their ability to non-oxidatively kill unopsonized Candida yeast cells [32, 40], which contributes to the collective impairment of effector function of neutrophils in the setting of CARD9 deficiency during CNS fungal disease. Given the refractory nature of fungal disease in these patients, adjunct GM-CSF treatment has been successfully used in some CARD9-deficient patients [41–43], while others have required allogeneic HSCT for infection control [44].

CARD9 is an intracellular adaptor molecule that relays C-type lectin receptor-dependent fungal sensing signals downstream of the spleen tyrosine kinase Syk [45, 46]. Of note, the Syk inhibitor fostamatinib is currently administered in >40 clinical trials (www.clinicaltrials.gov) in patients with various acquired conditions such as rheumatoid arthritis, acute leukemia, lymphoma, graft-versus-host disease, solid tumors that themselves alone predispose patients to develop invasive candidiasis and other fungal infections [47]. In addition, fostamatinib was recently approved by the US Food and Drug Administration (FDA) for the treatment of patients with refractory chronic immune thrombocytopenia. Therefore, based on the profound susceptibility of CARD9-deficient patients to fungal disease, fostamatinib-treated individuals should be closely monitored clinically for the development of invasive candidiasis or other fungal infections that can also affect CARD9-deficient patients such as mucosal candidiasis, extrapulmonary aspergillosis, deep-seated dermatophytosis, and subcutaneous or CNS phaeohyphomycosis [34, 48–51].

Invasive aspergillosis

Effective immunity against invasive pulmonary aspergillosis relies on neutrophils and recruited monocytes [52]. CGD is the prototypic inherited immunodeficiency to predispose humans to invasive aspergillosis, with an associated lifetime infection risk of ~40–50% [53]. CGD patients display an enrichment of invasive aspergillosis caused by cryptic Aspergillus species that exhibit different clinical behavior compared to Aspergillus fumigatus, which typically causes infection in patients with iatrogenic immunosuppression [54]. The exception to the rule of CGD-associated invasive aspergillosis is deficiency in the p40phox subunit of the NADPH oxidase complex, which does not impair oxidative burst-dependent neutrophil fungal killing and, as a result, does not predispose to invasive aspergillosis in stark contrast to the deficiencies in the p22phox, p47phox, p67phox and gp91 subunits of the NADPH oxidase complex [55]. This observation is consistent with the previously reported finding that the degree of residual reactive oxygen species generation by CGD neutrophils directly correlates with favorable patient outcomes (including resistance to invasive infections) [56].

Besides CGD, other inherited monogenic disorders that predispose to invasive aspergillosis include GATA2 haploinsufficiency and STAT1 gain-of-function mutations, yet, the underlying immunological mechanisms of impaired phagocyte functions remain unknown in these patients [7]. Moreover, patients with autosomal-dominant hyper-IgE (Job’s) syndrome can develop invasive aspergillosis secondary to pre-existing structural lung disease, not because of neutrophil recruitment or effector function defects [57]. Recently, deep intronic STAT3 mutations that exert dominant-negative effects were reported, which would have been missed by Sanger sequencing of coding regions and essential splice sites [58], as well as splice site STAT3 mutations that lead to STAT3 haploinsufficiency [59], which may predispose to invasive aspergillosis that involves extrapulmonary tissues with sparing of the lungs.

Two inherited immunodeficiencies which lead to bacterial infection susceptibility but have not been known to predispose to invasive aspergillosis are X-linked agammaglobulinemia due to BTK mutations and genetic C5 deficiency. Strikingly, and unexpectedly based on the absence of invasive aspergillosis susceptibility in the corresponding monogenic disorders, administration of ibrutinib, a small-molecule kinase inhibitor of BTK, and of eculizumab, a humanized monoclonal antibody targeting C5a, has been associated with the emergence of invasive aspergillosis, including cases of disseminated disease involving the CNS. Ibrutinib treatment confers varying degrees of invasive aspergillosis risk ranging from ~3% to ~40% depending on the underlying malignancy and co-administration of corticosteroids and/or other immunosuppressive therapies [60–64]. BTK is expressed on myeloid phagocytes and ibrutinib-mediated inhibition of BTK on phagocytes impairs their anti-Aspergillus activity [65]. Notably, eculizumab-associated invasive aspergillosis was recently recognized in post-marketing surveillance of eculizumab-treated patients, which prompted the FDA to update the package insert with a warning for this infection, besides the well-recognized risk for infections due to encapsulated bacteria [66, 67]. The reasons for the discrepancy in the phenotypes between the aforementioned two monogenic disorders and the corresponding pharmacological inhibitors remain elusive and require investigation but may reflect the detrimental nature of acute blockade of the corresponding immune pathways relative to genetic defects, which manifest from birth and may allow for developing efficient compensatory immune mechanisms. Clinical awareness will be required to determine whether acute inhibition of other immune pathways by small-molecule kinase inhibitors or biologics may unexpectedly lead to invasive fungal infection susceptibility despite the absence of observed aspergillosis risk in the corresponding inherited monogenic disorders.

Invasive infections by endemic dimorphic fungi or Cryptococcus

Effective immunity against endemic dimorphic fungi (i.e., histoplasmosis, blastomycosis, coccidioidomycosis, paracoccidioidomycosis, talaromycosis) and cryptococcosis relies on the cross-talk between Th1-polarized lymphocytes and activated monocytes/macrophages, which engulf fungal elements for intracellular destruction [3].

Genetic defects across the IL-12/IFN-γ signaling pathway such as mutations in IL-12 or its receptors, mutations in IFN-γ receptors, loss-of-function STAT1, STAT3 or STAT4 mutations, GATA2 haploinsufficiency, and STAT1 gain-of-function mutations are well-recognized to predispose to varying degrees of susceptibility to invasive infections by the aforementioned intracellular fungi, but also by other intracellular pathogens such as nontuberculous mycobacteria of low virulence potential [3, 7]. These patients develop fungal infections that are disseminated, frequently involving the CNS and bone, and are typically refractory despite intensive antifungal therapy (reviewed in detail elsewhere [3, 7]).

Of interest, some of the infections by endemic dimorphic fungi are enriched in individuals of certain ethnic backgrounds, further attesting to the genetic risk modulation of host susceptibility to these infections [3]; it is unknown whether impaired responses of the IL-12/IFN-γ pathway underlie this susceptibility. Recently, whole genome sequencing analysis revealed that susceptibility to blastomycosis in individuals of Hmong ancestry is associated with genetic variants surrounding the IL6 locus [68]; whether patients treated with tocilizumab that inhibits IL-6 receptor signaling may be at risk for blastomycosis or other dimorphic fungal infections at endemic geographic areas warrants clinical surveillance. Importantly, concordant with the aforementioned inherited infection susceptibility of patients with mutations in the IL-12/IFN-γ signaling pathway, development of adult-onset severe invasive infections by endemic dimorphic fungi and Cryptococcus (particularly Cryptococcus gattii) has been attributed to neutralizing autoantibodies against IFN-γ and/or GM-CSF [69, 70]; notably, some of these autoantibodies are often enriched among Asian-born Asian patients, and may be amenable to rituximab-mediated depletion.

Non-monogenic immune-related gene variation and the risk of invasive fungal disease

Besides the aforementioned monogenic disorders that confer marked susceptibility to spontaneous fungal disease in humans, significant interest has been generated recently in identifying immune-related gene SNPs that may influence the risk of developing fungal disease and/or suffering worse outcome after fungal infection in patients with acquired immunodeficiency states. These SNPs alone do not confer susceptibility to spontaneous fungal infection like monogenic defects do, but they may augment the risk of fungal infection in the setting of hospitalization together with other associated iatrogenic pressures in acutely, critically ill patients.

Two such clinical examples are worthwhile highlighting. Approximately 3–5% of critically ill patients in the ICU develop invasive candidiasis despite the fact that the vast majority of ICU patients have similar iatrogenic risk factors for the infection such as central intravenous catheters, abdominal surgery, broad-spectrum antibiotics, total parenteral nutrition or immunosuppressive treatment [71]. Similarly, approximately 5–10% of allogeneic HSCT recipients develop invasive aspergillosis despite the fact that the vast majority of allogeneic HSCT recipients have ubiquitous exposure to inhaled Aspergillus conidia and similar iatrogenic risk factors for the infection such as neutropenia or corticosteroid use [72, 73]. Therefore, genetic variation may influence the risk of invasive candidiasis in ICU patients and of invasive aspergillosis in allogeneic HSCT recipients beyond that ascribed to conventional clinical or microbiological risk factors.

Several studies have revealed genetic associations that show promise for leading to improved risk assessment of patients at risk for these fungal infections, personalized antifungal prophylaxis, and/or optimized donor selection in the context of allogeneic HSCT. Although some of these studies have limitations that relate to population stratification biases, findings that may be in linkage disequilibrium with genetic variants in nearby genes that could themselves drive the observed phenotype, lack of multivariate analysis of the observed outcomes, and/or lack of validation studies in large patient cohorts, they provide important information on potential genetic factors that may predispose to invasive candidiasis in the ICU or to invasive aspergillosis following allogeneic HSCT. A few representative examples of such SNPs are briefly presented below; however, a detailed description of immune-related gene SNPs is beyond the scope of this review and has been discussed in detail elsewhere [6, 74–76].

Invasive candidiasis

Genetic variation in cytokines (IL10, IL12B, TNFA), chemokines (CCL8), chemokine receptors (CXCR1, CX3CR1), pattern recognition receptors (TLR1), type I interferon-dependent signaling molecules (STAT1, PSMB8, SP110), and other genetic loci (VAV3, CD58, TAGAP, LCE4A-C1orf68) has been associated with enhanced risk of developing invasive candidiasis in medical and/or surgical ICU patients and/or increased risk of suffering worse outcome following infection, namely greater mortality, persistent fungemia and/or disseminated infection beyond the bloodstream [77–84].

We previously showed that in a mouse model of invasive candidiasis, the monocyte/macrophage-targeted chemokine receptor Cx3cr1 is critical for host survival and control of tissue fungal proliferation [79]. Cx3cr1 promotes macrophage accumulation in the infected tissue, which is important for early macrophage-fungal interactions in vivo and fungal killing. Mechanistically, Cx3cr1 drives macrophage accumulation via regulating their survival by preventing caspase-3–dependent apoptosis, not by modulating their trafficking, differentiation or proliferation. In humans, we identified the dysfunctional allele CX3CR1-M280 to be associated in multivariate analysis of two independent patient cohorts with increased risk of both developing invasive candidiasis and suffering worse outcome following infection [79]. Mechanistically, consonant with the mouse data, primary human monocytes from individuals carrying CX3CR1-M280 in homozygosity had impaired survival attributed to their inability to induce cell-survival–promoting ERK and AKT activation upon CX3CL1 stimulation [85]. Importantly, individuals carrying the homozygous CX3CR1-M280 allele had decreased monocyte counts in peripheral blood [85]. Collectively, these mouse and human studies reveal the critical contribution of CX3CR1 in host defense against invasive (but not mucosal [86]) candidiasis and show that variation at the CX3CR1 locus is a novel population-based genetic factor that regulates monocyte signaling and influences the risk of invasive candidiasis in humans.

In addition, we demonstrated in a mouse model of invasive candidiasis that the neutrophil-targeted chemokine receptor Cxcr1 promotes host survival and fungal control [83]. Surprisingly, Cxcr1 drives neutrophil degranulation and non-oxidative burst-dependent fungal killing and is dispensable for neutrophil trafficking from the blood into the infected tissue. In humans, we identified the dysfunctional allele CXCR1-T276 to be associated in multivariate analysis with increased risk of suffering worse outcome after infection. Mechanistically, in agreement with the mouse data, primary human neutrophils from individuals carrying the heterozygous CXCR1-T276 allele had impaired neutrophil degranulation and fungal killing [83]. Taken together, these mouse and human data uncover the essential contribution of CXCR1 in systemic anti-Candida immunity and suggest that genetic variation at CXCR1 may be a novel population-based factor for risk stratification and prognostication of invasive candidiasis in ICU patients.

Importantly, a genome-wide association study evaluated ~120,000 SNPs across 186 genetic loci pertaining to immune-related conditions in hospitalized patients with candidemia relative to healthy control individuals [78]. This unbiased genomic approach discovered three novel genetic loci that increase the risk of developing candidemia, namely CD58, TAGAP, and LCE4A-C1orf68. Notably, patients who carried two or more high-risk SNPs within these loci had a ~20-fold increased risk of developing candidemia, indicating that combining SNPs from different genetic loci may act synergistically to increase the risk of infection [78]. Mechanistically, CD58 was shown to colocalize with Candida during phagocytosis and was critical for fungal uptake and killing by macrophages, whereas TAGAP was found to be important for TNF-α production and control of fungal growth in a mouse model of invasive candidiasis [78]. Given all the aforementioned genetic findings in recent years, an important direction of future research will be to develop screening genomic strategies to distinguish ICU patients who carry heightened genetic risk traits for invasive candidiasis and to design a placebo-controlled clinical trial to examine whether targeted echinocandin prophylaxis would prevent fungal infection in these high-risk individuals.

Invasive aspergillosis

Similar to invasive candidiasis, emerging literature has implicated genetic variation in either donors and/or recipients of allogeneic HSCT with a heightened risk of developing invasive aspergillosis post-HSCT. Specifically, genetic variation in soluble or membrane-bound fungal sensing molecules (TLR4, TLR6, CLEC1A, CLEC7A, NOD2, CD209, PTX3, PLG), cytokines (IFNG), cytokine receptors (TNFR1), chemokines (CXCL10), and other molecules (S100B) has been associated with increased risk of invasive aspergillosis following allogeneic HSCT [87–96].

A significant gene affecting susceptibility to invasive aspergillosis post-HSCT that is worthwhile expanding on is the soluble pattern recognition receptor long pentraxin 3 (PTX3) that recognizes Aspergillus conidia among other non-fungal microbial moieties. Ptx3-deficient mice are highly susceptible to invasive aspergillosis [97] and, in agreement, receipt of a HSCT from donors carrying a homozygous PTX3 haplotype that impairs normal alveolar expression of PTX3 was associated in multivariate analysis of two independent patient cohorts with increased risk of developing invasive aspergillosis following HSCT [87]. The association between PTX3 genetic variation and the risk of invasive aspergillosis was subsequently extended to other disease cohorts such as in patients with chronic obstructive pulmonary disease or solid organ transplant recipients [98, 99]. Mechanistically, primary human neutrophils from individuals carrying the identified PTX3 haplotype exhibited impaired uptake and killing of Aspergillus conidia, and Aspergillus-infected lung tissue from these patients had impaired induction of pro-inflammatory cytokines [87, 100]. Importantly, restoration of PTX3 in neutrophils reverses the functional defects conferred by PTX3 deficiency and administration of recombinant PTX3 in Aspergillus-infected mice acts in synergy with triazole-based antifungal treatment when used in combination [87, 101]. Taken together, these data suggest that PTX3 genetic variation may serve as a novel precision medicine approach for both HSCT donor selection and for assessment of invasive aspergillosis risk, and that immunotherapies based on the delivery of PTX3 hold promise as potential adjunctive approaches in immunosuppressed patients.

Conclusions

Fungal infections cause significant morbidity and mortality in immunosuppressed patients despite antifungal treatment. Identifying patients at heightened risk for developing fungal disease and/or dismal outcome following infection has major implications in devising personalized strategies for risk stratification, prophylaxis, treatment, vaccination, monitoring, and prognostication. In recent years, a surge of studies has provided exciting new evidence of the potential contribution of variation in immune-related genes in influencing the risk of developing fungal disease and/or worse infection outcomes. Some of these immune-related genes reside within immunoregulatory pathways whose indispensable role in mammalian antifungal immunity was uncovered by the discovery of inherited monogenic disorders that cause spontaneous and profound fungal susceptibility in humans. Moving forward, the further integration of genomics into clinical practice may provide the opportunity to genetically screen high-risk immunosuppressed patients with the goal of identifying those with the highest probability of developing fungal disease, in whom precision medicine strategies for monitoring, prophylaxis or treatment may prove valuable in improving patient outcomes.