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Genetic Variation and Fungal Infection Risk: State of the Art

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Genetic Variation and Fungal Infection Risk: State of the Art Current Fungal Infection Reports (2019) 13:250–259 https://doi.org/10.1007/s12281-019-00362-6 EPIDEMIOLOGY OF FUNGAL INFECTIONS (T CHILLER AND J BADDLEY, SECTION EDITORS) Genetic Variation and Fungal Infection Risk: State of the Art Michail S. Lionakis1 Published online: 27 November 2019 # This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2019 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 infection 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 develop- ment 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. Keywords Fungal infection . Inherited immunodeficiency . Single nucleotide polymorphisms . Candidiasis . Aspergillosis . Genetic Introduction autoimmune diseases have led to a significant expansion of patient populations with iatrogenic immune suppression Despite continuous and ubiquitous exposure of humans to that are at risk for developing opportunistic fungal infections fungal microorganisms via the respiratory and gastrointestinal [2, 3]. mucosal surfaces and the skin, the majority of these fungal Despite the administration of antifungal drugs with potent encounters do not result in clinical disease. Endothermy and activity in vitro and in preclinical models, such fungal infec- homeothermy [1], and the induction of potent innate and adap- tions carry unacceptably high mortality rates and represent tive antifungal immune responses account for the resistance of unmet medical conditions. To improve fungal infection- mammals against most fungi [2, 3]. In the past few decades, associated patient outcomes, research efforts have primarily advances in clinical medicine that include the wider imple- focused on the discovery of novel effective antifungal agents mentation of hematopoietic stem cell or solid organ transplan- and the development of improved fungal-targeted diagnostic tation and the advent of effective chemotherapeutic and/or tests [4, 5]. More recently, increased research interest has been immunomodulatory treatments for neoplastic and generated in identifying individualized genetic factors that may enhance the risk of developing opportunistic fungal dis- ease and/or suffering worse outcomes from such infections. This article is part of the Topical Collection on Epidemiology of Fungal Infections Indeed, such knowledge could aid in devising precision med- icine strategies for risk stratification, prognostication, prophy- * Michail S. Lionakis laxis, vaccination, and/or treatment of patients at risk for op- [email protected] portunistic fungal infections. The research field of immunogenetic risk of fungal disease 1 Fungal Pathogenesis Section, Laboratory of Clinical Immunology & in humans has been largely ignited by the discovery and study Microbiology (LCIM), National Institute of Allergy & Infectious of inherited monogenic disorders that cause susceptibility to Diseases (NIAID), National Institutes of Health (NIH), 9000 Rockville Pike, Building 10, Room 12C103A, Bethesda, MD 20892, fungal infections, which has revealed important immunoreg- USA ulatory pathways that are specialized for the tissue-specific Curr Fungal Infect Rep (2019) 13:250–259 251 control of fungal pathogens [6–8]. The characterization of Additional inherited immunodeficiencies that are caused these pathways has catalyzed the study and identification of by mutations in other genes beyond the IL-17R signaling cas- SNPs in immune-related genes within the same or other sig- cade manifest with CMC by directly or indirectly affecting IL- naling pathways that may regulate the risk of fungal disease in 17R-dependent immune responses [8]. Such examples include patients with acquired immunodeficiency states. (but are not limited to) RORC mutations that impair Th17 cell Herein, I briefly outline current concepts pertaining to ge- development [20], autosomal-dominant hyper-IgE (Job’s) netic variation in immune pathways, whether monogenic or syndrome caused by dominant-negative STAT3 mutations that not, which regulate protective mucosal and systemic host de- abrogate STAT3-dependent RORγt-mediated generation of fense against the most common human fungal pathogens such Th17 cells [21], DOCK8 and CARD9 deficiencies that lead as Candida, Aspergillus, Cryptococcus, and endemic dimor- to defective Th17 cell differentiation [22, 23], STAT1 gain-of- phic fungi. This review discusses both (a) inborn errors of function mutations that impair Th17 cell development indi- immunity that underlie the spontaneous development of se- rectly via the induction of Th17 cell-inhibitory cytokine cir- vere human fungal disease and (b) immune-related gene SNPs cuits [24], and autoimmune polyendocrinopathy-candidiasis- that may modulate the risk of acquisition and/or outcome of ectodermal dystrophy (APECED) caused by AIRE mutations fungal infections in critically ill patients in the intensive care that feature neutralizing autoantibodies against Th17 cell- unit (ICU) and in patients with iatrogenic immunosuppression derived cytokines [25, 26], similar to patients with thymoma such as recipients of allogeneic hematopoietic stem cell trans- [27], who also develop mucosal candidiasis (reviewed in de- plantation (HSCT). tail elsewhere [3, 6–8]). Of interest, the introduction of IL-17R signaling-targeted biologics in the treatment of inflammatory and autoimmune Inherited Monogenic Disorders that disorders, primarily psoriasis and inflammatory bowel dis- Predispose to Chronic Mucocutaneous ease, has provided an additional layer of clinical evidence Candidiasis (CMC): the Key Role of IL-17 for the crucial role of this immunoregulatory pathway in mu- Receptor (IL-17R) Signaling cosal host defense against Candida in humans. Indeed, pa- tients who receive biologics that inhibit IL-12p40 In 2009, Sarah Gaffen’s laboratory was the first to demon- (ustekinumab), IL-23p19 (guselkumab, tildrakizumab), IL- strate the critical contribution of IL-17R signaling in host de- 17RA (brodalumab), IL-17A (secukinumab, ixekizumab), or fense against oropharyngeal candidiasis in mice [9••, 10, 11]. IL-17A/IL-17F (bimekizumab) occasionally develop refracto- Mechanistically, IL-17 cytokines (i.e., IL-17A, IL-17F) that ry mucocutaneous, but not systemic, candidiasis [28]. 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 Inherited Monogenic Disorders That surface of mucosal epithelial cells to induce the generation of Predispose to Invasive Fungal Infections: potent antimicrobial peptides (e.g., β-defensin 1, β-defensin Fungal Infection-Specific Differential 3, S100a8, S100a9) that exert direct anti-Candida activity and Contribution of Neutrophils, Mononuclear restrict mucosal fungal invasion [9–14]. Concordantly, in Phagocytes, and T Cells to Effective Host 2011, seminal work led by Jean-Laurent Casanova and Anne Defense Puel showed that genetic deficiency of IL-17R signaling in humans, in the form of either IL-17RA or IL-17F deficiencies, The identification and characterization of a plethora of predisposes to CMC, which is characterized by recurrent in- inherited monogenic disorders in recent years has highlighted fections of mucosal surfaces by Candida species [15]. Follow- the critical contribution of certain immunoregulatory path- up work by the same group discovered that inherited deficien- ways and immune cell subsets in host defense against invasive cies in IL-17RC or the IL-17R adaptor ACT1 (TRAF3IP2) infections by Candida, Aspergillus, endemic dimorphic fungi, also drive susceptibility to CMC in humans [16–18]. Some of and Cryptococcus [7]. these monogenic disorders (i.e., IL-17RA and ACT1 deficien- cies) can also manifest with staphylococcal skin disease and Invasive Candidiasis pulmonary bacterial infections, indicative of broader mucocu- taneous host defense impairments caused by IL-17R signaling Effective immunity against invasive candidiasis depends on defects [15–18]. Notably, consistent with the segregation of myeloid phagocyte recruitment and effector function [19, 29]. immune factors that are required for mucosal versus systemic The role of oxidative burst-dependent phagocyte fungal kill- control of Candida [3, 19], the aforementioned inborn errors ing in mediating control of invasive candidiasis has been long- of IL-17R-mediated immunity do not predispose patients to recognized given that a proportion of patients with complete systemic
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