scholarly journals Targeted Disruption of Nonribosomal Peptide Synthetasepes3Augments the Virulence of Aspergillus fumigatus

2011 ◽  
Vol 79 (10) ◽  
pp. 3978-3992 ◽  
Author(s):  
Karen A. O'Hanlon ◽  
Timothy Cairns ◽  
Deirdre Stack ◽  
Markus Schrettl ◽  
Elaine M. Bignell ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Opportunistic Pathogen ◽  
Immune Recognition ◽  
Phenotypic Analysis ◽  
Nonribosomal Peptide ◽  
Content Type ◽  
Targeted Gene Deletion ◽  
Wild Type Phenotype ◽  
Murine Tissue ◽  
Triacetylfusarinine C

ABSTRACTNonribosomal peptide synthesis (NRPS) is a documented virulence factor for the opportunistic pathogenAspergillus fumigatusand other fungi. Secreted or intracellularly located NRP products include the toxic molecule gliotoxin and the iron-chelating siderophores triacetylfusarinine C and ferricrocin. No structural or immunologically relevant NRP products have been identified in the organism. We investigated the function of the largest gene inA. fumigatus, which encodes the NRP synthetase Pes3 (AFUA_5G12730), by targeted gene deletion and extensive phenotypic analysis. It was observed that in contrast to other NRP synthetases, deletion ofpes3significantly increases the virulence ofA. fumigatus, whereby thepes3deletion strain (A. fumigatusΔpes3) exhibited heightened virulence (increased killing) in invertebrate (P< 0.001) and increased fungal burden (P= 0.008) in a corticosteroid model of murine pulmonary aspergillosis. Complementation restored the wild-type phenotype in the invertebrate model. Deletion ofpes3also resulted in increased susceptibility to the antifungal, voriconazole (P< 0.01), shorter germlings, and significantly reduced surface β-glucan (P= 0.0325). Extensive metabolite profiling revealed that Pes3 does not produce a secreted or intracellularly stored NRP inA. fumigatus. Macrophage infections and histological analysis of infected murine tissue indicate thatΔpes3heightened virulence appears to be mediated by aberrant innate immune recognition of the fungus. Proteome alterations inA. fumigatusΔpes3strongly suggest impaired germination capacity. Uniquely, our data strongly indicate a structural role for the Pes3-encoded NRP, a finding that appears to be novel for an NRP synthetase.

scholarly journals Nonribosomal Peptide Synthetase GenespesLandpes1Are Essential for Fumigaclavine C Production in Aspergillus fumigatus

2012 ◽  
Vol 78 (9) ◽  
pp. 3166-3176 ◽  
Author(s):  
Karen A. O'Hanlon ◽  
Lorna Gallagher ◽  
Markus Schrettl ◽  
Christoph Jöchl ◽  
Kevin Kavanagh ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Opportunistic Pathogen ◽  
Mass Spectrometry Analysis ◽  
Infection Model ◽  
Nonribosomal Peptide ◽  
Content Type ◽  
Spectrometry Analysis ◽  
Peptide Synthetases ◽  
Increased Sensitivity

ABSTRACTThe identity of metabolites encoded by the majority of nonribosomal peptide synthetases in the opportunistic pathogen,Aspergillus fumigatus, remains outstanding. We found that the nonribosomal peptide (NRP) synthetases PesL and Pes1 were essential for fumigaclavine C biosynthesis, the end product of the complex ergot alkaloid (EA) pathway inA. fumigatus. Deletion of eitherpesL(ΔpesL) orpes1(Δpes1) resulted in complete loss of fumigaclavine C biosynthesis, relatively increased production of fumitremorgins such as TR-2, fumitremorgin C and verruculogen, increased sensitivity to H2O2, and increased sensitivity to the antifungals, voriconazole, and amphotericin B. Deletion ofpesLresulted in severely reduced virulence in an invertebrate infection model (P< 0.001). These findings indicate that NRP synthesis plays an essential role in mediating the final prenylation step of the EA pathway, despite the apparent absence of NRP synthetases in the proposed EA biosynthetic cluster forA. fumigatus. Liquid chromatography/diode array detection/mass spectrometry analysis also revealed the presence of fumiquinazolines A to F in bothA. fumigatuswild-type and ΔpesLstrains. This observation suggests that alternative NRP synthetases can also function in fumiquinazoline biosynthesis, since PesL has been shown to mediate fumiquinazoline biosynthesisin vitro. Furthermore, we provide here the first direct link between EA biosynthesis and virulence, in agreement with the observed toxicity associated with EA exposure. Finally, we demonstrate a possible cluster cross-talk phenomenon, a theme which is beginning to emerge in the literature.

scholarly journals The LasB Elastase of Pseudomonas aeruginosa Acts in Concert with Alkaline Protease AprA To Prevent Flagellin-Mediated Immune Recognition

2015 ◽  
Vol 84 (1) ◽  
pp. 162-171 ◽  
Author(s):  
Fiordiligie Casilag ◽  
Anne Lorenz ◽  
Jonas Krueger ◽  
Frank Klawonn ◽  
Siegfried Weiss ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Alkaline Protease ◽  
Opportunistic Pathogen ◽  
Airway Epithelial Cells ◽  
Immune Recognition ◽  
Airway Epithelial ◽  
Content Type ◽  
Persistent Infections ◽  
Modulating Functions ◽  
Immune Detection

The opportunistic pathogenPseudomonas aeruginosais capable of establishing severe and persistent infections in various eukaryotic hosts. It encodes a wide array of virulence factors and employs several strategies to evade immune detection. In the present study, we screened the Harvard Medical School transposon mutant library ofP. aeruginosaPA14 for bacterial factors that modulate interleukin-8 responses in A549 human airway epithelial cells. We found that in addition to the previously identified alkaline protease AprA, the elastase LasB is capable of degrading exogenous flagellin under calcium-replete conditions and prevents flagellin-mediated immune recognition. Our results indicate that the production of two proteases with anti-flagellin activity provides a failsafe mechanism forP. aeruginosato ensure the maintenance of protease-dependent immune-modulating functions.

scholarly journals csrR, a Paralog and Direct Target of CsrA, Promotes Legionella pneumophila Resilience in Water

mBio ◽  
2015 ◽  
Vol 6 (3) ◽  
Author(s):  
Zachary D. Abbott ◽  
Helen Yakhnin ◽  
Paul Babitzke ◽  
Michele S. Swanson
Keyword(s):  
Legionella Pneumophila ◽  
Tap Water ◽  
Bacterial Species ◽  
Regulatory Protein ◽  
Opportunistic Pathogen ◽  
Water Systems ◽  
Phenotypic Analysis ◽  
Term Survival ◽  
Content Type

ABSTRACTCritical to microbial versatility is the capacity to express the cohort of genes that increase fitness in different environments.Legionella pneumophilaoccupies extensive ecological space that includes diverse protists, pond water, engineered water systems, and mammalian lung macrophages. One mechanism that equips this opportunistic pathogen to adapt to fluctuating conditions is a switch between replicative and transmissive cell types that is controlled by the broadly conserved regulatory protein CsrA. A striking feature of the legionellae surveyed is that each of 14 strains encodes 4 to 7csrA-like genes, candidate regulators of distinct fitness traits. Here we focus on the onecsrAparalog (lpg1593) that, like the canonicalcsrA, is conserved in all 14 strains surveyed. Phenotypic analysis revealed that long-term survival in tap water is promoted by thelpg1593locus, which we namecsrR(for “CsrA-similar protein forresilience”). As predicted by its GGA motif,csrRmRNA was bound directly by the canonical CsrA protein, as judged by electromobility shift and RNA-footprinting assays. Furthermore, CsrA repressed translation ofcsrRmRNAin vivo, as determined by analysis ofcsrR-gfpreporters,csrRmRNA stability in the presence and absence ofcsrAexpression, and mutation of the CsrA binding site identified on thecsrRmRNA. Thus, CsrA not only governs the transition from replication to transmission but also represses translation of its paralogcsrRwhen nutrients are available. We propose that, during prolonged starvation, relief of CsrA repression permits CsrR protein to coordinateL. pneumophila's switch to a cell type that is resilient in water supplies.IMPORTANCEPersistence ofL. pneumophilain water systems is a public health risk, and yet there is little understanding of the genetic determinants that equip this opportunistic pathogen to adapt to and survive in natural or engineered water systems. A potent regulator of this pathogen's intracellular life cycle is CsrA, a protein widely distributed among bacterial species that is understood quite well. Our finding that every sequencedL. pneumophilastrain carries severalcsrAparalogs—including two common to all isolates—indicates that the legionellae exploit CsrA regulatory switches for multiple purposes. Our discovery that one paralog, CsrR, is a target of CsrA that enhances survival in water is an important step toward understanding colonization of the engineered environment by pathogenicL. pneumophila.

scholarly journals SidL, an Aspergillus fumigatus Transacetylase Involved in Biosynthesis of the Siderophores Ferricrocin and Hydroxyferricrocin

2011 ◽  
Vol 77 (14) ◽  
pp. 4959-4966 ◽  
Author(s):  
Michael Blatzer ◽  
Markus Schrettl ◽  
Bettina Sarg ◽  
Herbert H. Lindner ◽  
Kristian Pfaller ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Fluorescent Protein ◽  
Iron Starvation ◽  
Fungal Virulence ◽  
Content Type ◽  
Siderophore Biosynthesis ◽  
Opportunistic Fungal Pathogen ◽  
Triacetylfusarinine C ◽  
Green Fluorescent ◽  
Biosynthetic Machinery

ABSTRACTThe opportunistic fungal pathogenAspergillus fumigatusproduces four types of siderophores, low-molecular-mass iron chelators: it excretes fusarinine C (FsC) and triacetylfusarinine C (TAFC) for iron uptake and accumulates ferricrocin (FC) for hyphal and hydroxyferricrocin (HFC) for conidial iron distribution and storage. Siderophore biosynthesis has recently been shown to be crucial for fungal virulence. Here we identified a new component of the fungal siderophore biosynthetic machinery: AFUA_1G04450, termed SidL. SidL is conserved only in siderophore-producing ascomycetes and shows similarity to transacylases involved in bacterial siderophore biosynthesis and theN5-hydroxyornithine:anhydromevalonyl coenzyme A-N5-transacylase SidF, which is essential for TAFC biosynthesis. Inactivation of SidL inA. fumigatusdecreased FC biosynthesis during iron starvation and completely blocked FC biosynthesis during iron-replete growth. In agreement with these findings, SidL deficiency blocked conidial accumulation of FC-derived HFC under iron-replete conditions, which delayed germination and decreased the size of conidia and their resistance to oxidative stress. Remarkably, thesidLgene is not clustered with other siderophore-biosynthetic genes, and its expression is not affected by iron availability. Tagging of SidL with enhanced green fluorescent protein suggested a cytosolic localization of the FC-biosynthetic machinery. Taken together, these data suggest that SidL is a constitutively activeN5-hydroxyornithine-acetylase required for FC biosynthesis, in particular under iron-replete conditions. Moreover, this study revealed the unexpected complexity of siderophore biosynthesis, indicating the existence of an additional, iron-repressedN5-hydroxyornithine-acetylase.

scholarly journals Growth of Aspergillus fumigatus in Biofilms in Comparison to Candida albicans

2022 ◽  
Vol 8 (1) ◽  
pp. 48
Author(s):  
Eefje Subroto ◽  
Jacq van Neer ◽  
Ivan Valdes ◽  
Hans de Cock
Keyword(s):  
Aspergillus Fumigatus ◽  
Defense Mechanisms ◽  
Molecular Mechanisms ◽  
Fungal Infections ◽  
Opportunistic Pathogen ◽  
Immune Recognition ◽  
Genetic Changes ◽  
Host Environment ◽  
Cell Dispersion ◽  
Protective Environment

Biofilm formation during infections with the opportunistic pathogen Aspergillus fumigatus can be very problematic in clinical settings, since it provides the fungal cells with a protective environment. Resistance against drug treatments, immune recognition as well as adaptation to the host environment allows fungal survival in the host. The exact molecular mechanisms behind most processes in the formation of biofilms are unclear. In general, the formation of biofilms can be categorized roughly in a few stages; adhesion, conidial germination and development of hyphae, biofilm maturation and cell dispersion. Fungi in biofilms can adapt to the in-host environment. These adaptations can occur on a level of phenotypic plasticity via gene regulation. However, also more substantial genetic changes of the genome can result in increased resistance and adaptation in the host, enhancing the survival chances of fungi in biofilms. Most research has focused on the development of biofilms. However, to tackle developing microbial resistance and adaptation in biofilms, more insight in mechanisms behind genetic adaptations is required to predict which defense mechanisms can be expected. This can be helpful in the development of novel and more targeted antifungal treatments to combat fungal infections.

scholarly journals Novel Biological Functions of the NsdC Transcription Factor in Aspergillus fumigatus

mBio ◽  
2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Patrícia Alves de Castro ◽  
Clara Valero ◽  
Jéssica Chiaratto ◽  
Ana Cristina Colabardini ◽  
Lakhansing Pardeshi ◽  
...  
Keyword(s):  
Cell Wall ◽  
Transcription Factor ◽  
Aspergillus Fumigatus ◽  
Sexual Reproduction ◽  
Rna Polymerase Ii ◽  
Vegetative Growth ◽  
Wall Structure ◽  
Immune Recognition ◽  
Biological Functions ◽  
Content Type

ABSTRACT The fungal zinc finger transcription factor NsdC is named after, and is best known for, its essential role in sexual reproduction (never in sexual development). In previous studies with Aspergillus nidulans, it was also shown to have roles in promotion of vegetative growth and suppression of asexual conidiation. In this study, the function of the nsdC homologue in the opportunistic human pathogen A. fumigatus was investigated. NsdC was again found to be essential for sexual development, with deletion of the nsdC gene in both MAT1-1 and MAT1-2 mating partners of a cross leading to complete loss of fertility. However, a functional copy of nsdC in one mating partner was sufficient to allow sexual reproduction. Deletion of nsdC also led to decreased vegetative growth and allowed conidiation in liquid cultures, again consistent with previous findings. However, NsdC in A. fumigatus was shown to have additional biological functions including response to calcium stress, correct organization of cell wall structure, and response to the cell wall stressors. Furthermore, virulence and host immune recognition were affected. Gene expression studies involving chromatin immunoprecipitation (ChIP) of RNA polymerase II (PolII) coupled to next-generation sequencing (Seq) revealed that deletion of nsdC resulted in changes in expression of over 620 genes under basal growth conditions. This demonstrated that this transcription factor mediates the activity of a wide variety of signaling and metabolic pathways and indicates that despite the naming of the gene, the promotion of sexual reproduction is just one among multiple roles of NsdC. IMPORTANCE Aspergillus fumigatus is an opportunistic human fungal pathogen and the main causal agent of invasive aspergillosis, a life-threatening infection especially in immunocompromised patients. A. fumigatus can undergo both asexual and sexual reproductive cycles, and the regulation of both cycles involves several genes and pathways. Here, we have characterized one of these genetic determinants, the NsdC transcription factor, which was initially identified in a screen of transcription factor null mutants showing sensitivity when exposed to high concentrations of calcium. In addition to its known essential roles in sexual reproduction and control of growth rate and asexual reproduction, we have shown in the present study that A. fumigatus NsdC transcription factor has additional previously unrecognized biological functions including calcium tolerance, cell wall stress response, and correct cell wall organization and functions in virulence and host immune recognition. Our results indicate that NsdC can play novel additional biological functions not directly related to its role played during sexual and asexual processes.

scholarly journals Azole Resistance of Environmental and Clinical Aspergillus fumigatus Isolates from Switzerland

2018 ◽  
Vol 62 (4) ◽  
Author(s):  
Arnaud Riat ◽  
Jérôme Plojoux ◽  
Katia Gindro ◽  
Jacques Schrenzel ◽  
Dominique Sanglard
Keyword(s):  
Aspergillus Fumigatus ◽  
Opportunistic Pathogen ◽  
Clinical Isolates ◽  
Resistant Isolate ◽  
Azole Resistance ◽  
Clinical Settings ◽  
Content Type ◽  
Azole Antifungals ◽  
First Time

ABSTRACT Aspergillus fumigatus is a ubiquitous opportunistic pathogen. This fungus can acquire resistance to azole antifungals due to mutations in the azole target ( cyp51A ). Recently, cyp51A mutations typical for environmental azole resistance acquisition (for example, TR 34 /L98H) have been reported. These mutations can also be found in isolates recovered from patients. Environmental azole resistance acquisition has been reported on several continents. Here we describe, for the first time, the occurrence of azole-resistant A. fumigatus isolates of environmental origin in Switzerland with cyp51A mutations, and we show that these isolates can also be recovered from a few patients. While the TR 34 /L98H mutation was dominant, a single azole-resistant isolate exhibited a cyp51A mutation (G54R) that was reported only for clinical isolates. In conclusion, our study demonstrates that azole resistance with an environmental signature is present in environments and patients of Swiss origin and that mutations believed to be unique to clinical settings are now also observed in the environment.

scholarly journals Proteome Analysis Reveals the Conidial Surface Protein CcpA Essential for Virulence of the Pathogenic FungusAspergillus fumigatus

mBio ◽  
2018 ◽  
Vol 9 (5) ◽  
Author(s):  
Vera Voltersen ◽  
Matthew G. Blango ◽  
Sahra Herrmann ◽  
Franziska Schmidt ◽  
Thorsten Heinekamp ◽  
...  
Keyword(s):  
Cell Wall ◽  
Aspergillus Fumigatus ◽  
Surface Structure ◽  
Fungal Spores ◽  
Fungal Spore ◽  
Invasive Infection ◽  
Immune Recognition ◽  
Wild Type ◽  
Content Type ◽  
Conidial Surface

ABSTRACTAspergillus fumigatusis a common airborne fungal pathogen of humans and a significant source of mortality in immunocompromised individuals. Here, we provide the most extensive cell wall proteome profiling to date ofA. fumigatusresting conidia, the fungal morphotype pertinent to first contact with the host. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we identified proteins within the conidial cell wall by hydrogen-fluoride (HF)–pyridine extraction and proteins exposed on the surface using a trypsin-shaving approach. One protein, designatedconidialcell wallproteinA(CcpA), was identified by both methods and was found to be nearly as abundant as hydrophobic rodlet layer-forming protein RodA. CcpA, an amphiphilic protein, like RodA, peaks in expression during sporulation on resting conidia. Despite high cell wall abundance, the cell surface structure of ΔccpAresting conidia appeared normal. However, trypsin shaving of ΔccpAconidia revealed novel surface-exposed proteins not detected on conidia of the wild-type strain. Interestingly, the presence of swollen ΔccpAconidia led to higher activation of neutrophils and dendritic cells than was seen with wild-type conidia and caused significantly less damage to epithelial cellsin vitro. In addition, virulence was highly attenuated when cortisone-treated, immunosuppressed mice were infected with ΔccpAconidia. CcpA-specific memory T cell responses were detectable in healthy human donors naturally exposed toA. fumigatusconidia, suggesting a role for CcpA as a structural protein impacting conidial immunogenicity rather than possessing a protein-intrinsic immunosuppressive effect. Together, these data suggest that CcpA serves as a conidial stealth protein by altering the conidial surface structure to minimize innate immune recognition.IMPORTANCEThe mammalian immune system relies on recognition of pathogen surface antigens for targeting and clearance. In the absence of immune evasion strategies, pathogen clearance is rapid. In the case ofAspergillus fumigatus, the successful fungus must avoid phagocytosis in the lung to establish invasive infection. In healthy individuals, fungal spores are cleared by immune cells; however, in immunocompromised patients, clearance mechanisms are impaired. Here, using proteome analyses, we identified CcpA as an important fungal spore protein involved in pathogenesis.A. fumigatuslacking CcpA was more susceptible to immune recognition and prompt eradication and, consequently, exhibited drastically attenuated virulence. In infection studies, CcpA was required for virulence in infected immunocompromised mice, suggesting that it could be used as a possible immunotherapeutic or diagnostic target in the future. In summary, our report adds a protein to the list of those known to be critical to the complex fungal spore surface environment and, more importantly, identifies a protein important for conidial immunogenicity during infection.

scholarly journals Reducing Aspergillus fumigatus Virulence through Targeted Dysregulation of the Conidiation Pathway

mBio ◽  
2020 ◽  
Vol 11 (1) ◽  
Author(s):  
James I. P. Stewart ◽  
Vinicius M. Fava ◽  
Joshua D. Kerkaert ◽  
Adithya S. Subramanian ◽  
Fabrice N. Gravelat ◽  
...  
Keyword(s):  
Mouse Model ◽  
Aspergillus Fumigatus ◽  
Vegetative Growth ◽  
Wall Structure ◽  
Invasive Infection ◽  
Phenotypic Analysis ◽  
Airborne Spores ◽  
Content Type

ABSTRACT Inhalation of conidia of the opportunistic mold Aspergillus fumigatus by immunocompromised hosts can lead to invasive pulmonary disease. Inhaled conidia that escape immune defenses germinate to form filamentous hyphae that invade lung tissues. Conidiation rarely occurs during invasive infection of the human host, allowing the bulk of fungal energy to be directed toward vegetative growth. We hypothesized that forced induction of conidiation during infection can suppress A. fumigatus vegetative growth, impairing the ability of this organism to cause disease. To study the effects of conidiation pathway dysregulation on A. fumigatus virulence, a key transcriptional regulator of conidiation (brlA) was expressed under the control of a doxycycline-inducible promoter. Time- and dose-dependent brlA overexpression was observed in response to doxycycline both in vitro and in vivo. Exposure of the inducible brlA overexpression strain to low doses of doxycycline under vegetative growth conditions in vitro induced conidiation, whereas high doses arrested growth. Overexpression of brlA attenuated A. fumigatus virulence in both an invertebrate and mouse model of invasive aspergillosis. RNA sequencing studies and phenotypic analysis revealed that brlA overexpression results in altered cell signaling, amino acid, and carbohydrate metabolism, including a marked upregulation of trehalose biosynthesis and a downregulation in the biosynthesis of the polysaccharide virulence factor galactosaminogalactan. This proof of concept study demonstrates that activation of the conidiation pathway in A. fumigatus can reduce virulence and suggests that brlA-inducing small molecules may hold promise as a new class of therapeutics for A. fumigatus infection. IMPORTANCE The mold Aspergillus fumigatus reproduces by the production of airborne spores (conidia), a process termed conidiation. In immunocompromised individuals, inhaled A. fumigatus conidia can germinate and form filaments that penetrate and damage lung tissues; however, conidiation does not occur during invasive infection. In this study, we demonstrate that forced activation of conidiation in filaments of A. fumigatus can arrest their growth and impair the ability of this fungus to cause disease in both an insect and a mouse model of invasive infection. Activation of conidiation was linked to profound changes in A. fumigatus metabolism, including a shift away from the synthesis of polysaccharides required for cell wall structure and virulence in favor of carbohydrates used for energy storage and stress resistance. Collectively, these findings suggest that activation of the conidiation pathway may be a promising approach for the development of new agents to prevent or treat A. fumigatus infection.

scholarly journals Contribution of Galactofuranose to the Virulence of the Opportunistic Pathogen Aspergillus fumigatus

2008 ◽  
Vol 7 (8) ◽  
pp. 1268-1277 ◽  
Author(s):  
Philipp S. Schmalhorst ◽  
Sven Krappmann ◽  
Wouter Vervecken ◽  
Manfred Rohde ◽  
Meike Müller ◽  
...  
Keyword(s):  
Cell Wall ◽  
Invasive Aspergillosis ◽  
Aspergillus Fumigatus ◽  
Mammalian Cells ◽  
Opportunistic Pathogen ◽  
Fungal Cell ◽  
Targeted Gene Deletion ◽  
Key Enzyme ◽  
Glucan Synthesis

ABSTRACT The filamentous fungus Aspergillus fumigatus is responsible for a lethal disease called invasive aspergillosis that affects immunocompromised patients. This disease, like other human fungal diseases, is generally treated by compounds targeting the primary fungal cell membrane sterol. Recently, glucan synthesis inhibitors were added to the limited antifungal arsenal and encouraged the search for novel targets in cell wall biosynthesis. Although galactomannan is a major component of the A. fumigatus cell wall and extracellular matrix, the biosynthesis and role of galactomannan are currently unknown. By a targeted gene deletion approach, we demonstrate that UDP-galactopyranose mutase, a key enzyme of galactofuranose metabolism, controls the biosynthesis of galactomannan and galactofuranose containing glycoconjugates. The glfA deletion mutant generated in this study is devoid of galactofuranose and displays attenuated virulence in a low-dose mouse model of invasive aspergillosis that likely reflects the impaired growth of the mutant at mammalian body temperature. Furthermore, the absence of galactofuranose results in a thinner cell wall that correlates with an increased susceptibility to several antifungal agents. The UDP-galactopyranose mutase thus appears to be an appealing adjunct therapeutic target in combination with other drugs against A. fumigatus. Its absence from mammalian cells indeed offers a considerable advantage to achieve therapeutic selectivity.

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