RESUMEN
In the last few decades, the AIDS pandemic and the significant advances in the medical management of individuals with neoplastic and inflammatory conditions have resulted in a dramatic increase in the population of immunosuppressed patients with opportunistic, life-threatening fungal infections. The parallel development of clinically relevant mouse models of fungal disease and the discovery and characterization of several inborn errors of immune-related genes that underlie inherited human susceptibility to opportunistic mycoses have significantly expanded our understanding of the innate and adaptive immune mechanisms that protect against ubiquitous fungal exposures. This review synthesizes immunological knowledge derived from basic mouse studies and from human cohorts and provides an overview of mammalian antifungal host defenses that show promise for informing therapeutic and vaccination strategies for vulnerable patients.
Asunto(s)
Interacciones Huésped-Patógeno/inmunología , Micosis/inmunología , Micosis/microbiología , Síndrome de Inmunodeficiencia Adquirida/complicaciones , Síndrome de Inmunodeficiencia Adquirida/inmunología , Inmunidad Adaptativa , Animales , Susceptibilidad a Enfermedades , Vacunas Fúngicas/inmunología , Hongos/inmunología , Humanos , Sistema Inmunológico/citología , Sistema Inmunológico/inmunología , Sistema Inmunológico/metabolismo , Inmunidad Innata , Huésped Inmunocomprometido , Inmunoterapia , Micosis/prevención & control , Micosis/terapia , Transducción de SeñalRESUMEN
The gut fungal community represents an essential element of human health, yet its functional and metabolic potential remains insufficiently elucidated, largely due to the limited availability of reference genomes. To address this gap, we presented the cultivated gut fungi (CGF) catalog, encompassing 760 fungal genomes derived from the feces of healthy individuals. This catalog comprises 206 species spanning 48 families, including 69 species previously unidentified. We explored the functional and metabolic attributes of the CGF species and utilized this catalog to construct a phylogenetic representation of the gut mycobiome by analyzing over 11,000 fecal metagenomes from Chinese and non-Chinese populations. Moreover, we identified significant common disease-related variations in gut mycobiome composition and corroborated the associations between fungal signatures and inflammatory bowel disease (IBD) through animal experimentation. These resources and findings substantially enrich our understanding of the biological diversity and disease relevance of the human gut mycobiome.
Asunto(s)
Hongos , Microbioma Gastrointestinal , Micobioma , Animales , Humanos , Masculino , Ratones , Heces/microbiología , Hongos/genética , Hongos/clasificación , Hongos/aislamiento & purificación , Genoma Fúngico/genética , Genómica , Enfermedades Inflamatorias del Intestino/microbiología , Enfermedades Inflamatorias del Intestino/genética , Metagenoma , Filogenia , Femenino , Adulto , Persona de Mediana EdadRESUMEN
Fungal communities (the mycobiota) are an integral part of the gut microbiota, and the disruption of their integrity contributes to local and gut-distal pathologies. Yet, the mechanisms by which intestinal fungi promote homeostasis remain unclear. We characterized the mycobiota biogeography along the gastrointestinal tract and identified a subset of fungi associated with the intestinal mucosa of mice and humans. Mucosa-associated fungi (MAF) reinforced intestinal epithelial function and protected mice against intestinal injury and bacterial infection. Notably, intestinal colonization with a defined consortium of MAF promoted social behavior in mice. The gut-local effects on barrier function were dependent on IL-22 production by CD4+ T helper cells, whereas the effects on social behavior were mediated through IL-17R-dependent signaling in neurons. Thus, the spatial organization of the gut mycobiota is associated with host-protective immunity and epithelial barrier function and might be a driver of the neuroimmune modulation of mouse behavior through complementary Type 17 immune mechanisms.
Asunto(s)
Microbioma Gastrointestinal , Micobioma , Receptores de Interleucina-17/metabolismo , Conducta Social , Animales , Hongos , Inmunidad Mucosa , Mucosa Intestinal , Ratones , Membrana MucosaRESUMEN
Plant immunity is activated upon pathogen perception and often affects growth and yield when it is constitutively active. How plants fine-tune immune homeostasis in their natural habitats remains elusive. Here, we discover a conserved immune suppression network in cereals that orchestrates immune homeostasis, centering on a Ca2+-sensor, RESISTANCE OF RICE TO DISEASES1 (ROD1). ROD1 promotes reactive oxygen species (ROS) scavenging by stimulating catalase activity, and its protein stability is regulated by ubiquitination. ROD1 disruption confers resistance to multiple pathogens, whereas a natural ROD1 allele prevalent in indica rice with agroecology-specific distribution enhances resistance without yield penalty. The fungal effector AvrPiz-t structurally mimics ROD1 and activates the same ROS-scavenging cascade to suppress host immunity and promote virulence. We thus reveal a molecular framework adopted by both host and pathogen that integrates Ca2+ sensing and ROS homeostasis to suppress plant immunity, suggesting a principle for breeding disease-resistant, high-yield crops.
Asunto(s)
Calcio/metabolismo , Depuradores de Radicales Libres/metabolismo , Proteínas Fúngicas/metabolismo , Oryza/inmunología , Inmunidad de la Planta , Proteínas de Plantas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Sistemas CRISPR-Cas/genética , Membrana Celular/metabolismo , Resistencia a la Enfermedad/genética , Modelos Biológicos , Oryza/genética , Enfermedades de las Plantas/inmunología , Proteínas de Plantas/genética , Unión Proteica , Estabilidad Proteica , Reproducción , Especificidad de la Especie , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitinación , Zea mays/inmunologíaRESUMEN
Antibodies mediate natural and vaccine-induced immunity against viral and bacterial pathogens, whereas fungi represent a widespread kingdom of pathogenic species for which neither vaccine nor neutralizing antibody therapies are clinically available. Here, using a multi-kingdom antibody profiling (multiKAP) approach, we explore the human antibody repertoires against gut commensal fungi (mycobiota). We identify species preferentially targeted by systemic antibodies in humans, with Candida albicans being the major inducer of antifungal immunoglobulin G (IgG). Fungal colonization of the gut induces germinal center (GC)-dependent B cell expansion in extraintestinal lymphoid tissues and generates systemic antibodies that confer protection against disseminated C. albicans or C. auris infection. Antifungal IgG production depends on the innate immunity regulator CARD9 and CARD9+CX3CR1+ macrophages. In individuals with invasive candidiasis, loss-of-function mutations in CARD9 are associated with impaired antifungal IgG responses. These results reveal an important role of gut commensal fungi in shaping the human antibody repertoire through CARD9-dependent induction of host-protective antifungal IgG.
Asunto(s)
Anticuerpos Antifúngicos/inmunología , Proteínas Adaptadoras de Señalización CARD/metabolismo , Tracto Gastrointestinal/inmunología , Tracto Gastrointestinal/microbiología , Inmunidad , Inmunoglobulina G/inmunología , Micobioma/inmunología , Animales , Linfocitos B/inmunología , Candida albicans/inmunología , Candidiasis/inmunología , Candidiasis/microbiología , Heces/microbiología , Centro Germinal/inmunología , Humanos , Ratones Endogámicos C57BL , Fagocitos/metabolismo , Polimorfismo de Nucleótido Simple/genética , Unión Proteica , Transducción de SeñalRESUMEN
Th17 cells provide protection at barrier tissues but may also contribute to immune pathology. The relevance and induction mechanisms of pathologic Th17 responses in humans are poorly understood. Here, we identify the mucocutaneous pathobiont Candida albicans as the major direct inducer of human anti-fungal Th17 cells. Th17 cells directed against other fungi are induced by cross-reactivity to C. albicans. Intestinal inflammation expands total C. albicans and cross-reactive Th17 cells. Strikingly, Th17 cells cross-reactive to the airborne fungus Aspergillus fumigatus are selectively activated and expanded in patients with airway inflammation, especially during acute allergic bronchopulmonary aspergillosis. This indicates a direct link between protective intestinal Th17 responses against C. albicans and lung inflammation caused by airborne fungi. We identify heterologous immunity to a single, ubiquitous member of the microbiota as a central mechanism for systemic induction of human anti-fungal Th17 responses and as a potential risk factor for pulmonary inflammatory diseases.
Asunto(s)
Candida albicans/inmunología , Células Th17/inmunología , Células Th17/metabolismo , Aspergillus fumigatus/inmunología , Aspergillus fumigatus/patogenicidad , Candida albicans/patogenicidad , Reacciones Cruzadas/inmunología , Fibrosis Quística/inmunología , Fibrosis Quística/microbiología , Humanos , Inmunidad , Inmunidad Heteróloga/inmunología , Células Th17/fisiologíaRESUMEN
STING (stimulator of interferon genes) exerts protective cellular responses to viral infection via induction of interferon production and autophagy. Here, we report the role of STING in modulating the immune responses toward fungal infection. Upon Candida albicans stimulation, STING transited alongside the endoplasmic reticulum (ER) to the phagosomes. In phagosomes, STING directly bound with Src via the N-terminal 18 amino acids of STING, and this binding prevented Src from recruiting and phosphorylating Syk. Consistently, Syk-associated signaling and production of pro-inflammatory cytokines and chemokines were increased in mouse BMDCs (bone-marrow-derived dendritic cells) lacking STING with fungal treatment. STING deficiency improved anti-fungal immunity in systemic C. albicans infection. Importantly, administration of the N-terminal 18-aa (amino acid) peptide of STING improved host outcomes in disseminated fungal infection. Overall, our study identifies a previously unrecognized function of STING in negatively regulating anti-fungal immune responses and offers a potential therapeutic strategy for controlling C. albicans infection.
Asunto(s)
Nucleótidos , Transducción de Señal , Animales , Ratones , Citocinas/metabolismo , Inmunidad Innata , Interferones/metabolismo , Nucleótidos/metabolismo , Fagosomas/metabolismo , Fagosomas/microbiologíaRESUMEN
Invasive fungal infections are associated with high mortality rates, and the lack of efficient treatment options emphasizes an urgency to identify underlying disease mechanisms. We report that disseminated Candida albicans infection is facilitated by interleukin-1 receptor antagonist (IL-1Ra) secreted from macrophages in two temporally and spatially distinct waves. Splenic CD169+ macrophages release IL-1Ra into the bloodstream, impeding early neutrophil recruitment. IL-1Ra secreted by monocyte-derived tissue macrophages further impairs pathogen containment. Therapeutic IL-1Ra neutralization restored the functional competence of neutrophils, corrected maladapted hyper-inflammation, and eradicated the otherwise lethal infection. Conversely, augmentation of macrophage-secreted IL-1Ra by type I interferon severely aggravated disease mortality. Our study uncovers how a fundamental immunoregulatory mechanism mediates the high disease susceptibility to invasive candidiasis. Furthermore, interferon-stimulated IL-1Ra secretion may exacerbate fungal dissemination in human patients with secondary candidemia. Macrophage-secreted IL-1Ra should be considered as an additional biomarker and potential therapeutic target in severe systemic candidiasis.
Asunto(s)
Proteína Antagonista del Receptor de Interleucina 1 , Sepsis , Humanos , Candida albicans , Macrófagos , Receptores de Interleucina-1RESUMEN
Fungal-mediated disease progression and antifungal drug efficacy are significantly impacted by the dynamic infection microenvironment. At the site of infection, oxygen often becomes limiting and induces a hypoxia response in both the fungal pathogen and host cells. The fungal hypoxia response impacts several important aspects of fungal biology that contribute to pathogenesis, virulence, antifungal drug susceptibility, and ultimately infection outcomes. In this review, we summarize recent advances in understanding the molecular mechanisms of the hypoxia response in the most common human fungal pathogens, discuss potential therapeutic opportunities, and highlight important areas for future research.
Asunto(s)
Antifúngicos , Hipoxia , Humanos , Antifúngicos/farmacología , Antifúngicos/uso terapéutico , Virulencia , Progresión de la EnfermedadRESUMEN
Fungi are opportunists: They particularly require a defect of immunity to cause severe or disseminated disease. While often secondary to an apparent iatrogenic cause, fungal diseases do occur in the absence of one, albeit infrequently. These rare cases may be due to an underlying genetic immunodeficiency that can present variably in age of onset, severity, or other infections, and in the absence of a family history of disease. They may also be due to anti-cytokine autoantibodies. This review provides a background on how human genetics or autoantibodies underlie cases of susceptibility to severe or disseminated fungal disease. Subsequently, the lessons learned from these inborn errors of immunity marked by fungal disease (IEI-FD) provide a framework to begin to mechanistically decipher fungal syndromes, potentially paving the way for precision therapy of the mycoses.
Asunto(s)
Síndromes de Inmunodeficiencia , Micosis , Humanos , Genómica , Hongos , AutoanticuerposRESUMEN
Cryptococcus species utilize a variety of sexual reproduction mechanisms, which generate genetic diversity, purge deleterious mutations, and contribute to their ability to occupy myriad environmental niches and exhibit a range of pathogenic potential. The bisexual and unisexual cycles of pathogenic Cryptococcus species are stimulated by properties associated with their environmental niches and proceed through well-characterized signaling pathways and corresponding morphological changes. Genes governing mating are encoded by the mating-type (MAT) loci and influence pathogenesis, population dynamics, and lineage divergence in Cryptococcus. MAT has undergone significant evolutionary changes within the Cryptococcus genus, including transition from the ancestral tetrapolar state in nonpathogenic species to a bipolar mating system in pathogenic species, as well as several internal reconfigurations. Owing to the variety of established sexual reproduction mechanisms and the robust characterization of the evolution of mating and MAT in this genus, Cryptococcus species provide key insights into the evolution of sexual reproduction.
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Cryptococcus/fisiología , Cryptococcus/patogenicidad , Genes del Tipo Sexual de los Hongos , Reproducción/fisiología , Evolución Biológica , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Genética de Población , Interacciones Huésped-Patógeno , Humanos , Esporas Fúngicas/patogenicidad , Esporas Fúngicas/fisiologíaRESUMEN
Invasive fungal infections are emerging diseases that kill over 1.5 million people per year worldwide. With the increase of immunocompromised populations, the incidence of invasive fungal infections is expected to continue to rise. Vaccines for viral and bacterial infectious diseases have had a transformative impact on human health worldwide. However, no fungal vaccines are currently in clinical use. Recently, interest in fungal vaccines has grown significantly. One Candida vaccine has completed phase 2 clinical trials, and research on vaccines against coccidioidomycosis continues to advance. Additionally, multiple groups have discovered various Cryptococcus mutant strains that promote protective responses to subsequent challenge in mouse models. There has also been progress in antibody-mediated fungal vaccines. In this review, we highlight recent fungal vaccine research progress, outline the wealth of data generated, and summarize current research for both fungal biology and immunology studies relevant to fungal vaccine development. We also review technological advancements in vaccine development and highlight the future prospects of a human vaccine against invasive fungal infections.
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Vacunas Fúngicas , Infecciones Fúngicas Invasoras , Vacunas , Animales , Humanos , Inmunidad , Ratones , Desarrollo de VacunasRESUMEN
The last several decades have witnessed a surge in drug-resistant fungal infections that pose a serious threat to human health. While there is a limited arsenal of drugs that can be used to treat systemic infections, scientific advances have provided renewed optimism for the discovery of novel antifungals. The development of chemical-genomic assays using Saccharomyces cerevisiae has provided powerful methods to identify the mechanism of action of molecules in a living cell. Advances in molecular biology techniques have enabled complementary assays to be developed in fungal pathogens, including Candida albicans and Cryptococcus neoformans. These approaches enable the identification of target genes for drug candidates, as well as genes involved in buffering drug target pathways. Here, we examine yeast chemical-genomic assays and highlight how such resources can be utilized to predict the mechanisms of action of compounds, to study virulence attributes of diverse fungal pathogens, and to bolster the antifungal pipeline.
Asunto(s)
Antifúngicos , Cryptococcus neoformans , Antifúngicos/farmacología , Candida albicans/genética , Cryptococcus neoformans/genética , Genómica/métodos , Humanos , Saccharomyces cerevisiaeRESUMEN
Fungi, including yeasts, molds, and mushrooms, proliferate on decaying matter and then adopt quiescent forms once nutrients are depleted. This review explores how fungi use sirtuin deacetylases to sense and respond appropriately to changing nutrients. Because sirtuins are NAD+-dependent deacetylases, their activity is sensitive to intracellular NAD+ availability. This allows them to transmit information about a cell's metabolic state on to the biological processes they influence. Fungal sirtuins are primarily known to deacetylate histones, repressing transcription and modulating genome stability. Their target genes include those involved in NAD+ homeostasis, metabolism, sporulation, secondary metabolite production, and virulence traits of pathogenic fungi. By targeting different genes over evolutionary time, sirtuins serve as rewiring points that allow organisms to evolve novel responses to low NAD+ stress by bringing relevant biological processes under the control of sirtuins.
Asunto(s)
Sirtuinas , Epigénesis Genética , Hongos/genética , Hongos/metabolismo , Expresión Génica , NAD/metabolismo , Sirtuinas/genética , Sirtuinas/metabolismoRESUMEN
The continuous expansion of immunocompromised patient populations at-risk for developing life-threatening opportunistic fungal infections in recent decades has helped develop a deeper understanding of antifungal host defenses, which has provided the foundation for eventually devising immune-based targeted interventions in the clinic. This review outlines how genetic variation in certain immune pathway-related genes may contribute to the observed clinical variability in the risk of acquisition and/or severity of fungal infections and how immunogenetic-based patient stratification may enable the eventual development of personalized strategies for antifungal prophylaxis and/or vaccination. Moreover, this review synthesizes the emerging cytokine-based, cell-based, and other immunotherapeutic strategies that have shown promise as adjunctive therapies for boosting or modulating tissue-specific antifungal immune responses in the context of opportunistic fungal infections.
Asunto(s)
Antifúngicos , Micosis , Humanos , Antifúngicos/uso terapéutico , Inmunoterapia , CitocinasRESUMEN
The human immune system uses an arsenal of effector mechanisms to prevent and counteract infections. Yet, some fungal species are extremely successful as human pathogens, which can be attributed to a wide variety of strategies by which these fungi evade, exploit, and modulate the immune system. These fungal pathogens normally are either harmless commensals or environmental fungi. In this review we discuss how commensalism, but also life in an environmental niche without human contact, can drive the evolution of diverse and specialized immune evasion mechanisms. Correspondingly, we discuss the mechanisms contributing to the ability of these fungi to cause superficial to life-threatening infections.
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Interacciones Huésped-Patógeno , Evasión Inmune , Humanos , Macrófagos , HongosRESUMEN
Fusarium, Aspergillus and Candida are important fungal pathogens that cause visual impairment and blindness in the USA and worldwide. This review will summarize the epidemiology and clinical features of corneal infections and discuss the immune and inflammatory responses that play an important role in clinical disease. In addition, we describe fungal virulence factors that are required for survival in infected corneas, and the activities of neutrophils in fungal killing, tissue damage and cytokine production.
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Fusarium , Queratitis , Humanos , Hongos , Córnea/microbiología , Córnea/patología , Queratitis/microbiología , Queratitis/patología , Fusarium/fisiología , NeutrófilosRESUMEN
RNA interference (RNAi) is a fundamental regulatory pathway with a wide range of functions, including regulation of gene expression and maintenance of genome stability. Although RNAi is widespread in the fungal kingdom, well-known species, such as the model yeast Saccharomyces cerevisiae, have lost the RNAi pathway. Until now evidence has been lacking for a fully functional RNAi pathway in Candida albicans, a human fungal pathogen considered critically important by the World Health Organization. Here, we demonstrated that the widely used C. albicans reference strain (SC5314) contains an inactivating missense mutation in the gene encoding for the central RNAi component Argonaute. In contrast, most other C. albicans isolates contain a canonical Argonaute protein predicted to be functional and RNAi-active. Indeed, using high-throughput small and long RNA sequencing combined with seamless CRISPR/Cas9-based gene editing, we demonstrate that an active C. albicans RNAi machinery represses expression of subtelomeric gene families. Thus, an intact and functional RNAi pathway exists in C. albicans, highlighting the importance of using multiple reference strains when studying this dangerous pathogen.
Asunto(s)
Candida albicans , Edición Génica , Humanos , Candida albicans/genética , Interferencia de ARN , Saccharomyces cerevisiae/metabolismo , Inestabilidad GenómicaRESUMEN
Antiviral RNA interference (RNAi) is conserved from yeasts to mammals. Dicer recognizes and cleaves virus-derived double-stranded RNA (dsRNA) and/or structured single-stranded RNA (ssRNA) into small-interfering RNAs, which guide effector Argonaute to homologous viral RNAs for digestion and inhibit virus replication. Thus, Argonaute is believed to be essential for antiviral RNAi. Here, we show Argonaute-independent, Dicer-dependent antiviral defense against dsRNA viruses using Cryphonectria parasitica (chestnut blight fungus), which is a model filamentous ascomycetous fungus and hosts a variety of viruses. The fungus has two dicer-like genes (dcl1 and dcl2) and four argonaute-like genes (agl1 to agl4). We prepared a suite of single to quadruple agl knockout mutants with or without dcl disruption. We tested these mutants for antiviral activities against diverse dsRNA viruses and ssRNA viruses. Although both DCL2 and AGL2 worked as antiviral players against some RNA viruses, DCL2 without argonaute was sufficient to block the replication of other RNA viruses. Overall, these results indicate the existence of a Dicer-alone defense and different degrees of susceptibility to it among RNA viruses. We discuss what determines the great difference in susceptibility to the Dicer-only defense.
Asunto(s)
Virus ARN , Ribonucleasa III , Ribonucleasa III/metabolismo , Ribonucleasa III/genética , Virus ARN/inmunología , Virus ARN/genética , Proteínas Argonautas/metabolismo , Proteínas Argonautas/genética , Ascomicetos/virología , Interferencia de ARN , Replicación Viral/genética , ARN Viral/metabolismo , ARN Viral/genética , Proteínas Fúngicas/metabolismo , Proteínas Fúngicas/genética , ARN Bicatenario/metabolismoRESUMEN
It is extremely rare that a single virus crosses host barriers across multiple kingdoms. Based on phylogenetic and paleovirological analyses, it has previously been hypothesized that single members of the family Partitiviridae could cross multiple kingdoms. Partitiviridae accommodates members characterized by their simple bisegmented double-stranded RNA genome; asymptomatic infections of host organisms; the absence of an extracellular route for entry in nature; and collectively broad host range. Herein, we show the replicability of single fungal partitiviruses in three kingdoms of host organisms: Fungi, Plantae, and Animalia. Betapartitiviruses of the phytopathogenic fungusRosellinia necatrix could replicate in protoplasts of the carrot (Daucus carota), Nicotiana benthamiana and Nicotiana tabacum, in some cases reaching a level detectable by agarose gel electrophoresis. Moreover, betapartitiviruses showed more robust replication than the tested alphapartitiviruses. One of the fungal betapartitiviruses, RnPV18, could persistently and stably infect carrot plants regenerated from virion-transfected protoplasts. Both alpha- and betapartitiviruses, although with different host preference, could replicate in two insect cell lines derived from the fall armyworm Spodoptera frugiperda and the fruit fly Drosophila melanogaster. Our results indicate the replicability of single partitiviruses in members of three kingdoms and provide insights into virus adaptation, host jumping, and evolution.