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PLoS Pathogens Jul 2021Aspergillus fumigatus is an opportunistic human pathogen that causes aspergillosis, a spectrum of environmentally acquired respiratory illnesses. It has a cosmopolitan... (Review)
Review
Aspergillus fumigatus is an opportunistic human pathogen that causes aspergillosis, a spectrum of environmentally acquired respiratory illnesses. It has a cosmopolitan distribution and exists in the environment as a saprotroph on decaying plant matter. Azoles, which target Cyp51A in the ergosterol synthesis pathway, are the primary class of drugs used to treat aspergillosis. Azoles are also used to combat plant pathogenic fungi. Recently, an increasing number of azole-naive patients have presented with pan-azole-resistant strains of A. fumigatus. The TR34/L98H and TR46/Y121F/T289A alleles in the cyp51A gene are the most common ones conferring pan-azole resistance. There is evidence that these mutations arose in agricultural settings; therefore, numerous studies have been conducted to identify azole resistance in environmental A. fumigatus and to determine where resistance is developing in the environment. Here, we summarize the global occurrence of azole-resistant A. fumigatus in the environment based on available literature. Additionally, we have created an interactive world map showing where resistant isolates have been detected and include information on the specific alleles identified, environmental settings, and azole fungicide use. Azole-resistant A. fumigatus has been found on every continent, except for Antarctica, with the highest number of reports from Europe. Developed environments, specifically hospitals and gardens, were the most common settings where azole-resistant A. fumigatus was detected, followed by soils sampled from agricultural settings. The TR34/L98H resistance allele was the most common in all regions except South America where the TR46/Y121F/T289A allele was the most common. A major consideration in interpreting this survey of the literature is sampling bias; regions and environments that have been extensively sampled are more likely to show greater azole resistance even though resistance could be more prevalent in areas that are under-sampled or not sampled at all. Increased surveillance to pinpoint reservoirs, as well as antifungal stewardship, is needed to preserve this class of antifungals for crop protection and human health.
Topics: Animals; Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Azoles; Disease Reservoirs; Drug Resistance, Fungal; Humans
PubMed: 34324607
DOI: 10.1371/journal.ppat.1009711 -
Nature Communications Jul 2023Aspergillus fumigatus, an opportunistic human pathogen, frequently infects the lungs of people with cystic fibrosis and is one of the most common causes of...
Aspergillus fumigatus, an opportunistic human pathogen, frequently infects the lungs of people with cystic fibrosis and is one of the most common causes of infectious-disease death in immunocompromised patients. Here, we construct 252 strain-specific, genome-scale metabolic models of this important fungal pathogen to study and better understand the metabolic component of its pathogenic versatility. The models show that 23.1% of A. fumigatus metabolic reactions are not conserved across strains and are mainly associated with amino acid, nucleotide, and nitrogen metabolism. Profiles of non-conserved reactions and growth-supporting reaction fluxes are sufficient to differentiate strains, for example by environmental or clinical origin. In addition, shotgun metagenomics analysis of sputum from 40 cystic fibrosis patients (15 females, 25 males) before and after diagnosis with an A. fumigatus colonization suggests that the fungus shapes the lung microbiome towards a more beneficial fungal growth environment associated with aromatic amino acid availability and the shikimate pathway. Our findings are starting points for the development of drugs or microbiome intervention strategies targeting fungal metabolic needs for survival and colonization in the non-native environment of the human lung.
Topics: Male; Female; Humans; Aspergillus fumigatus; Cystic Fibrosis; Lung; Microbiota
PubMed: 37474497
DOI: 10.1038/s41467-023-39982-5 -
Frontiers in Immunology 2023is a well-known opportunistic pathogen that causes a range of diseases including the often-fatal disease, invasive pulmonary aspergillosis (IPA), in immunocompromised...
BACKGROUND
is a well-known opportunistic pathogen that causes a range of diseases including the often-fatal disease, invasive pulmonary aspergillosis (IPA), in immunocompromised populations. The severity of IPA is dependent on both host- and pathogen-derived signaling molecules that mediate host immunity and fungal growth. Oxylipins are bioactive oxygenated fatty acids known to influence host immune response and developmental programs. synthesizes 8-HODE and 5,8-diHODE that have structural similarities to 9-HODE and 13-HODE, which are known ligands of the host G-protein-coupled receptor G2A (GPR132).
MATERIALS AND METHODS
Oxylipins were extracted from infected lung tissue to assess fungal oxylipin production and the Pathhunter β-arrestin assay was used to assess agonist and antagonist activity by fungal oxylipins on G2A. An immunocompetent model of infection was used to assess changes in survival and immune responses for G2A-/- mice.
RESULTS
Here we report that oxylipins are produced in lung tissue of infected mice and ligand assays suggest 8-HODE is a G2A agonist and 5,8-diHODE is a partial antagonist. To address the hypothesis that G2A could be involved in the progression of IPA, we assessed the response of G2A-/- mice to infection. G2A-/- mice showed a survival advantage over wild-type mice; this was accompanied by increased recruitment of G2A-/- neutrophils and increased levels of inflammatory markers in -infected lungs.
CONCLUSIONS
We conclude that G2A suppresses host inflammatory responses to although it remains unclear if fungal oxylipins are involved in G2A activities.
Topics: Animals; Mice; Aspergillus fumigatus; Invasive Pulmonary Aspergillosis; Oxylipins; Receptors, G-Protein-Coupled
PubMed: 37435068
DOI: 10.3389/fimmu.2023.1173544 -
Virulence Dec 2019spp and particularly the species are the causative agents of invasive aspergillosis, a progressive necrotizing pneumonia that occurs in immunocompromised patients. The... (Review)
Review
spp and particularly the species are the causative agents of invasive aspergillosis, a progressive necrotizing pneumonia that occurs in immunocompromised patients. The limited efficacy of currently available antifungals has led to interest in a better understanding of the molecular mechanisms underlying the pathogenesis of invasive aspergillosis in order to identify new therapeutic targets for this devastating disease. The exopolysaccharide galactosaminogalactan (GAG) plays an important role in the pathogenesis of experimental invasive aspergillosis. The present review article summarizes our current understanding of GAG composition and synthesis and the molecular mechanisms whereby GAG promotes virulence. Promising directions for future research and the prospect of GAG as both a therapy and therapeutic target are reviewed.
Topics: Animals; Aspergillosis; Aspergillus fumigatus; Biofilms; Biosynthetic Pathways; Fungal Proteins; Host-Pathogen Interactions; Humans; Mice; Polysaccharides; Virulence; Virulence Factors
PubMed: 30667338
DOI: 10.1080/21505594.2019.1568174 -
Virulence Dec 2021is the leading cause of life-threatening invasive mold infections in immunocompromised individuals. This ubiquitous saprophyte possesses several natural attributes...
is the leading cause of life-threatening invasive mold infections in immunocompromised individuals. This ubiquitous saprophyte possesses several natural attributes allowing it to evade the immune system, including the ability to withstand high toxic Cu concentrations within the phagosomes of macrophages and neutrophils. We previously established that at high levels, Cu binds and activates the transcription factor AceA, which upregulates the expression of the Cu exporter CrpA to expel excess Cu. Deletion of or result in extreme Cu sensitivity and attenuated virulence.To identify other elements participating in resistance to Cu, we performed a genome-wide analysis of the transcriptome by RNAseq to analyze the AceA-dependent response of to excess Cu. We deleted key genes whose transcription was strongly upregulated by high Cu, including those encoding homologs of the three Cu chaperones and . Detailed analysis of these genes indicates that in is an essential gene with a possible role in respiration, the gene product participates in reductive iron uptake and encodes the Cu chaperone activating Sod1. Interestingly, although the -null strain was extremely sensitive to high Cu and oxidative stress, it was not attenuated in virulence in a mouse model of invasive pulmonary aspergillosis.Our work provides (i) a detailed view of the genome-wide transcriptional response of to excess Cu, (ii) identification of the AceA-dependent transcriptome and (iii) analysis of the roles of the three Cu chaperones and
Topics: Animals; Aspergillus fumigatus; Copper; Fungal Proteins; Mice; Molecular Chaperones; Transcription Factors; Virulence
PubMed: 34468270
DOI: 10.1080/21505594.2021.1958057 -
Current Opinion in Microbiology Dec 2020The mammalian immune system can tune its inflammatory response to the threat level posed by an invading pathogen. It is well established that the host utilizes numerous... (Review)
Review
The mammalian immune system can tune its inflammatory response to the threat level posed by an invading pathogen. It is well established that the host utilizes numerous 'patterns of pathogenicity', such as microbial growth, invasion, and viability, to achieve this tuning during bacterial infections. This review discusses how this notion fits during fungal infection, particularly regarding Aspergillus fumigatus infection. Moreover, how the environmental niches filled by A. fumigatus may drive the evolution of the fungal traits responsible for inducing the strain-specific inflammatory responses that have been experimentally observed will be discussed. Moving forward understanding the mechanisms of the fungal strain-specific inflammatory response due to the initial interactions with the host innate immune system will be essential for enhancing our therapeutic options for the treatment of invasive fungal infections.
Topics: Animals; Aspergillosis; Aspergillus fumigatus; Fungal Proteins; Humans; Invasive Fungal Infections
PubMed: 32898768
DOI: 10.1016/j.mib.2020.08.004 -
Frontiers in Immunology 2022Species within the spp. cause a wide range of infections in humans, including invasive pulmonary aspergillosis, chronic pulmonary aspergillosis, and allergic... (Review)
Review
Species within the spp. cause a wide range of infections in humans, including invasive pulmonary aspergillosis, chronic pulmonary aspergillosis, and allergic bronchopulmonary aspergillosis, and are associated with high mortality rates. The incidence of pulmonary aspergillosis (PA) is on the rise, and the emergence of triazole-resistant spp. isolates, especially , limits the efficacy of mold-active triazoles. Therefore, host-directed and novel adjunctive therapies are required to more effectively combat PA. In this review, we focus on PA from a microbiome perspective. We provide a general overview of the effects of the lung and gut microbiomes on the growth of spp. and host immunity. We highlight the potential of the microbiome as a therapeutic target for PA.
Topics: Antifungal Agents; Aspergillus; Aspergillus fumigatus; Gastrointestinal Microbiome; Humans; Lung; Pulmonary Aspergillosis; Triazoles
PubMed: 36032147
DOI: 10.3389/fimmu.2022.988708 -
Nature Communications Jan 2024Aspergillus fumigatus is a saprophytic fungus that can cause a variety of human diseases known as aspergillosis. Mycotoxin gliotoxin (GT) production is important for its...
Aspergillus fumigatus is a saprophytic fungus that can cause a variety of human diseases known as aspergillosis. Mycotoxin gliotoxin (GT) production is important for its virulence and must be tightly regulated to avoid excess production and toxicity to the fungus. GT self-protection by GliT oxidoreductase and GtmA methyltransferase activities is related to the subcellular localization of these enzymes and how GT can be sequestered from the cytoplasm to avoid increased cell damage. Here, we show that GliT:GFP and GtmA:GFP are localized in the cytoplasm and in vacuoles during GT production. The Mitogen-Activated Protein kinase MpkA is essential for GT production and self-protection, interacts physically with GliT and GtmA and it is necessary for their regulation and subsequent presence in the vacuoles. The sensor histidine kinase SlnA is important for modulation of MpkA phosphorylation. Our work emphasizes the importance of MpkA and compartmentalization of cellular events for GT production and self-defense.
Topics: Humans; Aspergillus fumigatus; Gliotoxin; Fungal Proteins; Mitogen-Activated Protein Kinases; Aspergillosis
PubMed: 38167253
DOI: 10.1038/s41467-023-44329-1 -
The Journal of Clinical Investigation Mar 2023BACKGROUNDThe fungus Aspergillus fumigatus causes a variety of clinical phenotypes in patients with cystic fibrosis (pwCF). Th cells orchestrate immune responses against...
BACKGROUNDThe fungus Aspergillus fumigatus causes a variety of clinical phenotypes in patients with cystic fibrosis (pwCF). Th cells orchestrate immune responses against fungi, but the types of A. fumigatus-specific Th cells in pwCF and their contribution to protective immunity or inflammation remain poorly characterized.METHODSWe used antigen-reactive T cell enrichment (ARTE) to investigate fungus-reactive Th cells in peripheral blood of pwCF and healthy controls.RESULTSWe show that clonally expanded, high-avidity A. fumigatus-specific effector Th cells, which were absent in healthy donors, developed in pwCF. Individual patients were characterized by distinct Th1-, Th2-, or Th17-dominated responses that remained stable over several years. These different Th subsets target different A. fumigatus proteins, indicating that differential antigen uptake and presentation directs Th cell subset development. Patients with allergic bronchopulmonary aspergillosis (ABPA) are characterized by high frequencies of Th2 cells that cross-recognize various filamentous fungi.CONCLUSIONOur data highlight the development of heterogenous Th responses targeting different protein fractions of a single fungal pathogen and identify the development of multispecies cross-reactive Th2 cells as a potential risk factor for ABPA.FUNDINGGerman Research Foundation (DFG), under Germany's Excellence Strategy (EXC 2167-390884018 "Precision Medicine in Chronic Inflammation" and EXC 2051-390713860 "Balance of the Microverse"); Oskar Helene Heim Stiftung; Christiane Herzog Stiftung; Mukoviszidose Institut gGmb; German Cystic Fibrosis Association Mukoviszidose e.V; German Federal Ministry of Education and Science (BMBF) InfectControl 2020 Projects AnDiPath (BMBF 03ZZ0838A+B).
Topics: Aspergillus fumigatus; Cystic Fibrosis; Immunity; Aspergillosis, Allergic Bronchopulmonary; Immunoglobulin E; Inflammation
PubMed: 36701198
DOI: 10.1172/JCI161593 -
MBio Jun 2023Aspergillus fumigatus is an environmental fungus that can cause life-threatening pulmonary disease. Infections initiate when conidia are inhaled and land deep inside the...
Aspergillus fumigatus is an environmental fungus that can cause life-threatening pulmonary disease. Infections initiate when conidia are inhaled and land deep inside the small airways and alveoli of the lungs, where they interact with epithelial cells. These cells provide a physical barrier and secrete chemokines to attract innate immune cells to the site of infection. Melanin, a key constituent of the conidial cell wall, is required for the establishment of invasive infection due to its ability to inhibit the function of innate immune cells recruited to clear the infection. Here, we provide evidence for an additional mechanism by which A. fumigatus can alter host innate immune responses. infection of a normal human small airway epithelial cell line (HSAEC1-KT) caused a decrease in extracellular protein levels of CXCL10 and CCL20, two proinflammatory chemokines that are required for the host defense against aspergillosis, despite a dramatic increase in the levels of each mRNA. A. fumigatus depleted recombinant human CXCL10 and CCL20 from medium in the absence of host cells, suggesting that the block in accumulation is downstream of protein translation and secretion. Melanin is both necessary and sufficient for this chemokine-depleting activity because a dihydroxynaphthalene (DHN)-melanin-deficient strain of A. fumigatus is defective in depleting chemokines and purified melanin ghosts retain potent depletion activity. We propose that A. fumigatus, through the action of melanin, depletes important chemokines, thereby dampening the innate immune response to promote infection. Aspergillus fumigatus is the major airborne fungal pathogen that affects humans. In order to cause an invasive infection, inhaled spores must avoid killing by innate immune cells that are recruited to the site of infection. Understanding how A. fumigatus achieves immune evasion is important for the development of novel therapeutics. We provide evidence that melanin, a pigment contained in the spore cell wall, can remove certain chemokines from the extracellular space to suppress the host inflammatory response that is responsible for clearing fungal infection.
Topics: Humans; Melanins; Aspergillus fumigatus; Aspergillosis; Chemokines; Spores, Fungal
PubMed: 37067432
DOI: 10.1128/mbio.00194-23