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Clinical Microbiology Reviews Dec 2019is a saprotrophic fungus; its primary habitat is the soil. In its ecological niche, the fungus has learned how to adapt and proliferate in hostile environments. This... (Review)
Review
is a saprotrophic fungus; its primary habitat is the soil. In its ecological niche, the fungus has learned how to adapt and proliferate in hostile environments. This capacity has helped the fungus to resist and survive against human host defenses and, further, to be responsible for one of the most devastating lung infections in terms of morbidity and mortality. In this review, we will provide (i) a description of the biological cycle of ; (ii) a historical perspective of the spectrum of aspergillus disease and the current epidemiological status of these infections; (iii) an analysis of the modes of immune response against in immunocompetent and immunocompromised patients; (iv) an understanding of the pathways responsible for fungal virulence and their host molecular targets, with a specific focus on the cell wall; (v) the current status of the diagnosis of different clinical syndromes; and (vi) an overview of the available antifungal armamentarium and the therapeutic strategies in the clinical context. In addition, the emergence of new concepts, such as nutritional immunity and the integration and rewiring of multiple fungal metabolic activities occurring during lung invasion, has helped us to redefine the opportunistic pathogenesis of .
Topics: Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Disease Susceptibility; History, 21st Century; Host-Pathogen Interactions; Humans; Immunity; Immunocompromised Host; Public Health Surveillance; Treatment Outcome; Virulence
PubMed: 31722890
DOI: 10.1128/CMR.00140-18 -
International Journal of Antimicrobial... Jan 2020Aspergillus fumigatus is the main causal agent of invasive aspergillosis (IA), however other species of the genus can also cause IA, such as Aspergillus flavus,... (Review)
Review
Aspergillus fumigatus is the main causal agent of invasive aspergillosis (IA), however other species of the genus can also cause IA, such as Aspergillus flavus, Aspergillus terreus, Aspergillus niger and related cryptic species. This infectious disease mainly affects immunosuppressed patients and is linked to elevated mortality rates. As voriconazole is the treatment of choice for this condition, the relevant increase in the number of azole-resistant isolates in recent years has gathered alarming attention, as it also translates into an increase in clinical failures. In this review, we summarise and discuss the azole resistance molecular data described to date in the most clinically prevalent sections of Aspergillus, including mechanisms involving the target proteins Cyp51 and ATP-binding cassette (ABC) or major facilitator superfamily (MFS) efflux pumps. Other resistance mechanisms proposed but not yet fully characterised are also discussed.
Topics: ATP-Binding Cassette Transporters; Antifungal Agents; Aspergillus; Aspergillus fumigatus; Azoles; Cytochrome P450 Family 51; Drug Resistance, Fungal; Fungal Proteins; Humans; Voriconazole
PubMed: 31542320
DOI: 10.1016/j.ijantimicag.2019.09.011 -
Nature Microbiology Dec 2021Aspergillus fumigatus is an environmental saprobe and opportunistic human fungal pathogen. Despite an estimated annual occurrence of more than 300,000 cases of invasive...
Aspergillus fumigatus is an environmental saprobe and opportunistic human fungal pathogen. Despite an estimated annual occurrence of more than 300,000 cases of invasive disease worldwide, a comprehensive survey of the genomic diversity present in A. fumigatus-including the relationship between clinical and environmental isolates and how this genetic diversity contributes to virulence and antifungal drug resistance-has been lacking. In this study we define the pan-genome of A. fumigatus using a collection of 300 globally sampled genomes (83 clinical and 217 environmental isolates). We found that 7,563 of the 10,907 unique orthogroups (69%) are core and present in all isolates and the remaining 3,344 show presence/absence of variation, representing 16-22% of the genome of each isolate. Using this large genomic dataset of environmental and clinical samples, we found an enrichment for clinical isolates in a genetic cluster whose genomes also contain more accessory genes, including genes coding for transmembrane transporters and proteins with iron-binding activity, and genes involved in both carbohydrate and amino-acid metabolism. Finally, we leverage the power of genome-wide association studies to identify genomic variation associated with clinical isolates and triazole resistance as well as characterize genetic variation in known virulence factors. This characterization of the genomic diversity of A. fumigatus allows us to move away from a single reference genome that does not necessarily represent the species as a whole and better understand its pathogenic versatility, ultimately leading to better management of these infections.
Topics: Aspergillosis; Aspergillus fumigatus; Fungal Proteins; Genetic Variation; Genome, Fungal; Genome-Wide Association Study; Humans; Virulence Factors
PubMed: 34819642
DOI: 10.1038/s41564-021-00993-x -
Trends in Microbiology Jul 2020
Topics: Aspergillosis; Aspergillus fumigatus; Humans; Soil Microbiology
PubMed: 32544445
DOI: 10.1016/j.tim.2020.02.013 -
Current Topics in Microbiology and... 2020Dihydroxynaphthalene melanin (DHN-melanin) is an integral component of the conidial cell wall surface, which has a central role in the pathogenicity of the major human... (Review)
Review
Dihydroxynaphthalene melanin (DHN-melanin) is an integral component of the conidial cell wall surface, which has a central role in the pathogenicity of the major human airborne fungal pathogen Aspergillus fumigatus. Although the biosynthetic pathway for A. fumigatus DHN-melanin production has been well characterized, the molecular interactions of DHN-melanin with the immune system have been incompletely understood. Recent studies demonstrated that apart from concealing immunostimulatory cell wall polysaccharides, calcium sequestration by DHN-melanin inhibits essential host effector pathways regulating phagosome biogenesis and prevents A. fumigatus conidia killing by phagocytes. From the host perspective, DHN-melanin is specifically recognized by a C-type lectin receptor (MelLeC) present in murine endothelia and in human myeloid cells. Furthermore, DHN-melanin activates platelets and facilitates opsonophagocytosis by macrophages via binding to soluble pattern recognition receptors. Dissecting the dynamics of DHN-melanin organization on the fungal cell wall and the molecular interplay with the immune system will lead to a better understanding of A. fumigatus pathophysiology.
Topics: Animals; Aspergillosis; Aspergillus fumigatus; Cell Wall; Humans; Lectins, C-Type; Melanins; Naphthols; Receptors, Mitogen
PubMed: 32385534
DOI: 10.1007/82_2020_205 -
Current Topics in Microbiology and... 2020During infection, many fungal pathogens form biofilms within tissues or on biomedical devices. The growth of fungi within biofilms increases dramatically their... (Review)
Review
During infection, many fungal pathogens form biofilms within tissues or on biomedical devices. The growth of fungi within biofilms increases dramatically their resistance to both immune defences and antifungal therapies. In the last twenty years, studies have begun to shed light on many of the steps involved in biofilm synthesis and composition, revealing new antifungal strategies. This chapter will focus on the biofilm exopolysaccharides produced by A. fumigatus and C. albicans, the two main causes of human fungal infections. We will review the current state of our understanding of the structure, biosynthesis, and role of exopolysaccharides in biofilm development and function with a view to identifying future strategies for prophylaxis and treatment of these devastating infections.
Topics: Antifungal Agents; Aspergillus fumigatus; Biofilms; Candida albicans; Fungal Polysaccharides; Humans; Mycoses
PubMed: 32072265
DOI: 10.1007/82_2020_199 -
Mycopathologia Oct 2023Aspergillus fumigatus is one the most ubiquitous airborne opportunistic human fungal pathogens. Understanding its interaction with host immune system, composed of... (Review)
Review
Aspergillus fumigatus is one the most ubiquitous airborne opportunistic human fungal pathogens. Understanding its interaction with host immune system, composed of cellular and humoral arm, is essential to explain the pathobiology of aspergillosis disease spectrum. While cellular immunity has been well studied, humoral immunity has been poorly acknowledge, although it plays a crucial role in bridging the fungus and immune cells. In this review, we have summarized available data on major players of humoral immunity against A. fumigatus and discussed how they may help to identify at-risk individuals, be used as diagnostic tools or promote alternative therapeutic strategies. Remaining challenges are highlighted and leads are given to guide future research to better grasp the complexity of humoral immune interaction with A. fumigatus.
Topics: Humans; Aspergillus fumigatus; Immunity, Humoral; Aspergillosis
PubMed: 37289362
DOI: 10.1007/s11046-023-00742-0 -
Medical Mycology Aug 2020Aspergillosis is a respiratory fungal disease of importance in captive marine birds. The aim of this study was to describe the occurrence of aspergillosis in...
Aspergillosis is a respiratory fungal disease of importance in captive marine birds. The aim of this study was to describe the occurrence of aspergillosis in Thalassarche melanophris during rehabilitation events and to identify the etiological agent. All the albatrosses that were received for rehabilitation and died within a 2-year period were included in the study. The proportionate mortality rate caused by aspergillosis was 21.4% (3/14). One of the etiological agents was Aspergillus flavus/oryzae lineage, and the other was A. fumigatus sensu stricto. Our study suggests that aspergillosis can act as a limiting factor in the rehabilitation of albatrosses.
Topics: Animals; Aspergillosis; Aspergillus flavus; Aspergillus fumigatus; Birds; Female; Male; Oceans and Seas
PubMed: 31782484
DOI: 10.1093/mmy/myz122 -
International Journal of Biological... Dec 2023Fungal keratitis (FK) is a serious, potentially sight-threatening corneal infection, which is associated with poor prognosis. A20, also called TNFAIP3, plays significant...
Fungal keratitis (FK) is a serious, potentially sight-threatening corneal infection, which is associated with poor prognosis. A20, also called TNFAIP3, plays significant roles in the negative regulation of inflammation and immunity. However, the function of A20 in Aspergillus fumigatus (A. fumigatus) keratitis remains obscure. Herein, we found that the level of A20 is increased in human corneal epithelial cells (HCECs) and in mouse corneas with A. fumigatus infection, and that nuclear factor-κB (NF-κB) signaling is required for A20 upregulation. A20 overexpression inhibits A. fumigatus-mediated inflammatory responses, while A20 knockdown results in opposite effect. Mechanically, we showed that A20 inhibits NF-κB signaling and activates autophagy in infected HCECs. We also showed that inhibition of NF-κB signaling reverses the increased inflammatory responses in infected HCECs with A20 knockdown. Furthermore, autophagy blockage impedes the anti-inflammatory effect of A20 in A. fumigatus infected HCECs. Moreover, A20 ameliorates the corneal damage and inflammation in A. fumigatus infected mouse corneas. In conclusion, this study reveals that A20 alleviates A. fumigatus keratitis by activating autophagy and inhibiting NF-κB signaling. This suggests that exogenous use of A20 protein may be a potentially promising therapeutic strategy for FK treatment.
Topics: Animals; Mice; Humans; Aspergillus fumigatus; NF-kappa B; Epithelium, Corneal; Keratitis; Inflammation; Autophagy; Mice, Inbred C57BL
PubMed: 37879579
DOI: 10.1016/j.ijbiomac.2023.127640 -
Current Opinion in Infectious Diseases Aug 2020Although clinical outcomes in the treatment of aspergillosis have markedly improved with the availability of newer triazoles, the development of resistance to these... (Review)
Review
PURPOSE OF REVIEW
Although clinical outcomes in the treatment of aspergillosis have markedly improved with the availability of newer triazoles, the development of resistance to these antifungals, especially in Aspergillus fumigatus, is a growing concern. The purpose of this review is to provide an update on azole resistance mechanisms and their epidemiology in A. fumigatus, the clinical implications of azole resistance, and to discuss future treatment options against azole-resistant aspergillosis.
RECENT FINDINGS
Resistance may develop through either patient or environmental azole exposure. Environmental exposure is the most prevalent means of resistance development, and these isolates can cause disease in various at-risk groups, which now include those with influenza, and potentially COVID-19. Although current treatment options are limited, newer therapies are in clinical development. These include agents with novel mechanisms of action which have in vitro and in vivo activity against azole-resistant A. fumigatus.
SUMMARY
Azole-resistant A. fumigatus is an emerging threat that hampers our ability to successfully treat patients with aspergillosis. Certain geographic regions and patient populations appear to be at increased risk for this pathogen. As new patient groups are increasingly recognized to be at increased risk for invasive aspergillosis, studies to define the epidemiology and management of azole-resistant A. fumigatus are critically needed. While treatment options are currently limited, new agents under clinical development may offer hope.
Topics: Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Betacoronavirus; COVID-19; Coronavirus Infections; Drug Resistance, Multiple, Fungal; Environmental Exposure; Humans; Immunocompromised Host; Microbial Sensitivity Tests; Pandemics; Pneumonia, Viral; SARS-CoV-2; Triazoles
PubMed: 32657965
DOI: 10.1097/QCO.0000000000000662