scholarly journals Aspergillus fumigatus and Aspergillosis in 2019

2019 ◽  
Vol 33 (1) ◽  
Author(s):  
Jean-Paul Latgé ◽  
Georgios Chamilos

SUMMARY Aspergillus fumigatus 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 A. fumigatus; (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 Aspergillus 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 A. fumigatus.

2013 ◽  
Vol 12 (12) ◽  
pp. 1641-1652 ◽  
Author(s):  
Srijana Upadhyay ◽  
Guadalupe Torres ◽  
Xiaorong Lin

ABSTRACTAspergillus fumigatusproduces heavily melanized infectious conidia. The conidial melanin is associated with fungal virulence and resistance to various environmental stresses. This 1,8-dihydroxynaphthalene (DHN) melanin is synthesized by enzymes encoded in a gene cluster inA. fumigatus, including two laccases, Abr1 and Abr2. Although this gene cluster is not conserved in all aspergilli, laccases are critical for melanization in all species examined. Here we show that the expression ofA. fumigatuslaccases Abr1/2 is upregulated upon hyphal competency and drastically increased during conidiation. The Abr1 protein is localized at the surface of stalks and conidiophores, but not in young hyphae, consistent with the gene expression pattern and its predicted role. The induction of Abr1/2 upon hyphal competency is controlled by BrlA, the master regulator of conidiophore development, and is responsive to the copper level in the medium. We identified a developmentally regulated putative copper transporter, CtpA, and found that CtpA is critical for conidial melanization under copper-limiting conditions. Accordingly, disruption of CtpA enhanced the induction ofabr1andabr2, a response similar to that induced by copper starvation. Furthermore, nonpigmentedctpAΔ conidia elicited much stronger immune responses from the infected invertebrate hostGalleria mellonellathan the pigmentedctpAΔ or wild-type conidia. Such enhancement in elicitingGalleriaimmune responses was independent of thectpAΔ conidial viability, as previously observed for the DHN melanin mutants. Taken together, our findings indicate that both copper homeostasis and developmental regulators control melanin biosynthesis, which affects conidial surface properties that shape the interaction between this pathogen and its host.


2012 ◽  
Vol 11 (12) ◽  
pp. 1557-1567 ◽  
Author(s):  
Sven D. Willger ◽  
E. Jean Cornish ◽  
Dawoon Chung ◽  
Brittany A. Fleming ◽  
Margaret M. Lehmann ◽  
...  

ABSTRACTHypoxia is an environmental stress encountered byAspergillus fumigatusduring invasive pulmonary aspergillosis (IPA). The ability of this mold to adapt to hypoxia is important for fungal virulence and genetically regulated in part by the sterol regulatory element binding protein (SREBP) SrbA. SrbA is required for fungal growth in the murine lung and to ultimately cause lethal disease in murine models of IPA. Here we identified and partially characterized four genes (dscA,dscB,dscC, anddscD, here referred to asdscA-D) with previously unknown functions inA. fumigatusthat are orthologs of theSchizosaccharomyces pombegenesdsc1,dsc2,dsc3, anddsc4(dsc1-4), which encode a Golgi E3 ligase complex critical for SREBP activation by proteolytic cleavage.A. fumigatusnulldscA-Dmutants displayed remarkable defects in hypoxic growth and increased susceptibility to triazole antifungal drugs. Consistent with the confirmed role of these genes inS. pombe, both ΔdscAand ΔdscCresulted in reduced cleavage of the SrbA precursor protein inA. fumigatus. Inoculation of corticosteroid immunosuppressed mice with ΔdscAand ΔdscCstrains revealed that these genes are critical forA. fumigatusvirulence. Reintroduction of SrbA amino acids 1 to 425, encompassing the N terminus DNA binding domain, into the ΔdscAstrain was able to partially restore virulence, further supporting a mechanistic link between DscA and SrbA function. Thus, we have shown for the first time the importance of a previously uncharacterized group of genes inA. fumigatusthat mediate hypoxia adaptation, fungal virulence, and triazole drug susceptibility and that are likely linked to regulation of SrbA function.


2016 ◽  
Vol 84 (6) ◽  
pp. 1866-1878 ◽  
Author(s):  
Yakir Vaknin ◽  
Falk Hillmann ◽  
Rossana Iannitti ◽  
Netali Ben Baruch ◽  
Hana Sandovsky-Losica ◽  
...  

Aspergillus fumigatusis the most common pathogenic mold infecting humans and a significant cause of morbidity and mortality in immunocompromised patients. In invasive pulmonary aspergillosis,A. fumigatusspores are inhaled into the lungs, undergoing germination and invasive hyphal growth. The fungus occludes and disrupts the blood vessels, leading to hypoxia and eventual tissue necrosis. The ability of this mold to adapt to hypoxia is regulated in part by the sterol regulatory element binding protein (SREBP) SrbA and the DscA to DscD Golgi E3 ligase complex critical for SREBP activation by proteolytic cleavage. Loss of the genes encoding these proteins results in avirulence. To identify novel regulators of hypoxia sensing, we screened theNeurospora crassagene deletion library under hypoxia and identified a novel rhomboid family protease essential for hypoxic growth. Deletion of theA. fumigatusrhomboid homologrbdAresulted in an inability to grow under hypoxia, hypersensitivity to CoCl2, nikkomycin Z, fluconazole, and ferrozine, abnormal swollen tip morphology, and transcriptional dysregulation—accurately phenocopying deletion ofsrbA. In vivo,rbdAdeletion resulted in increased sensitivity to phagocytic killing, a reduced inflammatory Th1 and Th17 response, and strongly attenuated virulence. Phenotypic rescue of the ΔrbdAmutant was achieved by expression and nuclear localization of the N terminus of SrbA, including its HLH domain, further indicating that RbdA and SrbA act in the same signaling pathway. In summary, we have identified RbdA, a novel putative rhomboid family protease inA. fumigatusthat mediates hypoxia adaptation and fungal virulence and that is likely linked to SrbA cleavage and activation.


2011 ◽  
Vol 77 (14) ◽  
pp. 4959-4966 ◽  
Author(s):  
Michael Blatzer ◽  
Markus Schrettl ◽  
Bettina Sarg ◽  
Herbert H. Lindner ◽  
Kristian Pfaller ◽  
...  

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.


2009 ◽  
Vol 9 (3) ◽  
pp. 424-437 ◽  
Author(s):  
Jorge Amich ◽  
Rocío Vicentefranqueira ◽  
Fernando Leal ◽  
José Antonio Calera

ABSTRACTAspergillus fumigatushas three zinc transporter-encoding genes whose expression is regulated by both pH and the environmental concentration of zinc. We have previously reported that thezrfAandzrfBgenes ofA. fumigatusare transcribed at higher levels and are required for fungal growth under acidic zinc-limiting conditions whereas they are dispensable for growth in neutral or alkaline zinc-limiting media. Here we report that the transporter of the zinc uptake system that functions inA. fumigatusgrowing in neutral or alkaline environments is encoded byzrfC. The transcription ofzrfCoccurs divergently with respect to the adjacentaspf2gene, which encodes an immunodominant antigen secreted byA. fumigatus. The two genes—zrfCandaspf2—are required to different extents for fungal growth in alkaline and extreme zinc-limiting media. Indeed, these environmental conditions induce the simultaneous transcription of both genes mediated by the transcriptional regulators ZafA and PacC. ZafA upregulates the expression ofzrfCandaspf2under zinc-limiting conditions regardless of the ambient pH, whereas PacC represses the expression of these genes under acidic growth conditions. Interestingly, the mode of action of PacC forzrfC-aspf2transcription contrasts with the more widely accepted model for PacC function, according to which under alkaline growth conditions PacC would activate the transcription of alkaline-expressed genes but would repress the transcription of acid-expressed genes. In sum, this report provides a good framework for investigating several important aspects of the biology of species ofAspergillus, including the repression of alkaline genes by PacC at acidic pH and the interrelationship that must exist between tissue pH, metal availability in the host tissue, and fungal virulence.


mSphere ◽  
2020 ◽  
Vol 5 (5) ◽  
Author(s):  
Luyu Guan ◽  
Ruiyang Lu ◽  
Zhengjun Wu ◽  
Guowei Zhong ◽  
Shizhu Zhang

ABSTRACT The rise of drug resistance in fungal pathogens is becoming a serious problem owing to the limited number of antifungal drugs available. Identifying and targeting factors essential for virulence or development unique to fungal pathogens is one approach to develop novel treatments for fungal infections. In this study, we present the identification and functional characterization of a novel developmental regulator in Aspergillus fumigatus, AfMed15, which contained a conserved Med15_fungal domain, as determined by screening of a mutant library that contained more than 2,000 hygromycin-resistant A. fumigatus transformants. Downregulating the expression of Afmed15 abolished the conidiation and decreased the fungal virulence in an insect model. Strikingly, the overexpression of Afmed15 caused fungal death accompanied by intensive autophagy. RNA sequencing of an Afmed15 overexpression strain revealed that altered gene expression patterns were associated with carbon metabolism, energy metabolism, and translation. Interestingly, the addition of metal ions could partially rescue fungal death caused by the overexpression of Afmed15, indicating that disordered ion homeostasis is a potential reason for the fungal death caused by the overexpression of Afmed15. Considering that the precise expression of Afmed15 is crucial for fungal development, virulence, and survival and that no ortholog was found in humans, Afmed15 is an ideal target for antifungal-drug development. IMPORTANCE The identification and characterization of regulators essential for virulence or development constitute one approach for antifungal drug development. In this study, we screened and functionally characterized Afmed15, a novel developmental regulator in A. fumigatus. We demonstrate that the precise transcriptional expression of Afmed15 is crucial for fungal asexual development, virulence, and survival. Downregulating the expression of Afmed15 abolished the conidiation and decreased the fungal virulence in an insect model. In contrast, the overexpression of Afmed15 caused fungal death accompanied by intensive autophagy. Our study provides a foundation for further studies to identify compounds perturbing the expression of Afmed15 that may be used for the prevention of invasive A. fumigatus infections.


mSphere ◽  
2019 ◽  
Vol 4 (3) ◽  
Author(s):  
Arsa Thammahong ◽  
Sourabh Dhingra ◽  
Katherine M. Bultman ◽  
Joshua D. Kerkaert ◽  
Robert A. Cramer

ABSTRACTRegulation of fungal cell wall biosynthesis is critical to maintain cell wall integrity in dynamic fungal infection microenvironments. Genes involved in this response that impact fungal fitness and host immune responses remain to be fully defined. In this study, we observed that a yeastssd1homolog,ssdA, in the filamentous fungusAspergillus fumigatusis involved in trehalose and cell wall homeostasis. AnssdAnull mutant strain exhibited an increase in trehalose levels and a reduction in fungal colony growth rate. In contrast, overexpression ofssdAperturbed trehalose biosynthesis and reduced germination of conidia. ThessdAnull mutant strain was more resistant to cell wall-perturbing agents, while overexpression ofssdAincreased sensitivity. Overexpression ofssdAsignificantly increased chitin levels, and both loss and overexpression ofssdAaltered subcellular localization of the class V chitin synthase CsmA. Strikingly, overexpression ofssdAabolished adherence to abiotic surfaces and severely attenuated the virulence ofA. fumigatusin a murine model of invasive pulmonary aspergillosis. Despite the severein vitrofitness defects observed upon loss ofssdA, neither surface adherence nor murine survival was impacted. In conclusion,A. fumigatusSsdA plays a critical role in cell wall homeostasis impactingA. fumigatus-host interactions.IMPORTANCEThe incidence of life-threatening infections caused by the filamentous fungusAspergillus fumigatusis increasing along with an increase in the number of fungal strains resistant to contemporary antifungal therapies. The fungal cell wall and the associated carbohydrates required for its synthesis and maintenance are attractive drug targets given that many genes encoding proteins involved in cell wall biosynthesis and integrity are absent in humans. Importantly, genes and associated cell wall biosynthesis and homeostasis regulatory pathways remain to be fully defined inA. fumigatus. In this report, we identify SsdA as an important component of trehalose and fungal cell wall biosynthesis inA. fumigatusthat consequently impacts the host immune response and fungal virulence in animal models of infection.


mSphere ◽  
2019 ◽  
Vol 4 (5) ◽  
Author(s):  
Suresh Ambati ◽  
Emma C. Ellis ◽  
Jianfeng Lin ◽  
Xiaorong Lin ◽  
Zachary A. Lewis ◽  
...  

ABSTRACT Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus cause life-threatening candidiasis, cryptococcosis, and aspergillosis, resulting in several hundred thousand deaths annually. The patients at the greatest risk of developing these life-threatening invasive fungal infections have weakened immune systems. The vulnerable population is increasing due to rising numbers of immunocompromised individuals as a result of HIV infection or immunosuppressed individuals receiving anticancer therapies and/or stem cell or organ transplants. While patients are treated with antifungals such as amphotericin B, all antifungals have serious limitations due to lack of sufficient fungicidal effect and/or host toxicity. Even with treatment, 1-year survival rates are low. We explored methods of increasing drug effectiveness by designing fungicide-loaded liposomes specifically targeted to fungal cells. Most pathogenic fungi are encased in cell walls and exopolysaccharide matrices rich in mannans. Dectin-2 is a mammalian innate immune membrane receptor that binds as a dimer to mannans and signals fungal infection. We coated amphotericin-loaded liposomes with monomers of Dectin-2’s mannan-binding domain, sDectin-2. sDectin monomers were free to float in the lipid membrane and form dimers that bind mannan substrates. sDectin-2-coated liposomes bound orders of magnitude more efficiently to the extracellular matrices of several developmental stages of C. albicans, C. neoformans, and A. fumigatus than untargeted control liposomes. Dectin-2-coated amphotericin B-loaded liposomes reduced the growth and viability of all three species more than an order of magnitude more efficiently than untargeted control liposomes and dramatically decreased the effective dose. Future efforts focus on examining pan-antifungal targeted liposomal drugs in animal models of fungal diseases. IMPORTANCE Invasive fungal diseases caused by Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus have mortality rates ranging from 10 to 95%. Individual patient costs may exceed $100,000 in the United States. All antifungals in current use have serious limitations due to host toxicity and/or insufficient fungal cell killing that results in recurrent infections. Few new antifungal drugs have been introduced in the last 2 decades. Hence, there is a critical need for improved antifungal therapeutics. By targeting antifungal-loaded liposomes to α-mannans in the extracellular matrices secreted by these fungi, we dramatically reduced the effective dose of drug. Dectin-2-coated liposomes loaded with amphotericin B bound 50- to 150-fold more strongly to C. albicans, C. neoformans, and A. fumigatus than untargeted liposomes and killed these fungi more than an order of magnitude more efficiently. Targeting drug-loaded liposomes specifically to fungal cells has the potential to greatly enhance the efficacy of most antifungal drugs.


2013 ◽  
Vol 116 (1) ◽  
pp. 125-141 ◽  
Author(s):  
Manoj Dora ◽  
Dirk Van Goubergen ◽  
Maneesh Kumar ◽  
Adrienn Molnar ◽  
Xavier Gellynck

Purpose – Recent literature emphasizes the application of lean manufacturing practices to food processing industries in order to improve operational efficiency and productivity. Only a very limited number of studies have focused on the implementation of lean manufacturing practices within small and medium-sized enterprises (SMEs) operating in the food sector. The majority of these studies used the case study method and concentrated on individual lean manufacturing techniques geared towards resolving efficiency issues. This paper aims to analyze the status of the lean manufacturing practices and their benefits and barriers among European food processing SMEs. Design/methodology/approach – A structured questionnaire was developed to collect data. A total of 35 SMEs' representatives, mostly CEOs and operations managers, participated in the survey. The study investigated the role of two control variables in lean implementation: size of the company and country of origin. Findings – The findings show that lean manufacturing practice deployment in food processing SMEs is generally low and still evolving. However, some lean manufacturing practices are more prevalent than others; e.g. flow, pull and statistical process control are not widely used by the food processing SMEs, whereas total productive maintenance, employee involvement, and customer association are more widespread. The key barriers encountered by food SMEs in the implementation of lean manufacturing practices result from the special characteristics of the food sector, such as highly perishable products, complicated processing, extremely variable raw materials, recipes and unpredictable demand. In addition, lack of knowledge and resources makes it difficult for food processing SMEs to embark on the lean journey. Originality/value – The gap in the literature regarding the application of lean manufacturing in the food sector is identified and addressed in this study. The originality of this paper lies in analyzing the current status of the use of lean manufacturing practices among food SMEs in Europe and identifying potential barriers.


2017 ◽  
Vol 15 (3) ◽  
pp. 213-231
Author(s):  
Kiyoshi Murata ◽  
Yasunori Fukuta ◽  
Andrew A. Adams ◽  
Dang Ronghua

Purpose This study aims to investigate how Snowden’s revelations are viewed by young people in the People’s Republic of China (PRC) and Taiwan through questionnaire surveys of and follow-up interviews with university students in the two countries, taking into account the histories and current status of state surveillance in these countries and the current complicated and delicate cross-strait relationships. Design/methodology/approach Questionnaire surveys of 315 PRC and 111 Taiwanese university students (a majority studying in those places but a few studying abroad) and semi-structured follow-up interviews with 16 master’s course students from the PRC and one from Taiwan (all studying at Meiji University in Japan) were conducted, in addition to reviews of the literature on privacy and state surveillance in the PRC and Taiwan. The outcomes of the survey were statistically analysed and qualitative analyses of the interview results were also performed. Findings Youngsters living in the PRC had greater interest in and more knowledge about Snowden’s revelations than those living in Taiwan, and the revelations were positively evaluated in both countries as serving public interest. However, PRC students indicated they were less likely to emulate Snowden than those from Taiwan did. Originality/value This study is the first attempt to investigate the social impact of Snowden’s revelations on PRC and Taiwanese youngsters’ attitudes towards privacy and state surveillance as part of cross-cultural analyses between eight countries.


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