What makes aspergillus fumigatus a successful pathogen

Possibly, A. Taken together, our results show differences between A. These observations show a strong difference in the behavior of A. A higher internalization rate and a delay in germination will result in efficient hiding for clearance by the immune system and provides a latent conidia population that can cause an infection. The tight contact of A. Future studies with other Aspergillus species are needed to clarify if the observed advantages are unique for A.

NE and SO performed the experiments. All authors were involved in the analysis and interpretation of data. NE and SO wrote the manuscript. All authors approved the version to be published and agreed to be accountable for all aspects of the work. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. A Association of conidia in time, expressed as the number of conidia per A cells.

B Association of conidia after 4 h, expressed as the percentage of the total inoculum. C Internalization of conidia in time expressed as the number of conidia per A cell. D Internalization of total inoculum after 4 h. Data from four independent experiments from more than conidia per strain. A Conidia of A. LysoSensor TM green labeled acidic compartments. B Conidia of the white strains of A. C Conidia of the white strains of A. Data are from one of three representative experiments.

Nystatin Nyst protection assay was used to kill conidia outside the cells. Data from one of three representative experiments. A Start of conidial germination in the absence and presence of A cells; Arrows indicate germtubes.

Amin, S. Melanin dependent survival of Aspergillus fumigatus conidia in lung epithelial cells. Aoki, S. Oxygen as a possible tropic factor in hyphal growth of Candida albicans. Mycoscience 39, — Bathoorn, E. Involvement of the opportunistic pathogen Aspergillus tubingensis in osteomyelitis of the maxillary bone: a case report. BMC Infect. Bestebroer, J. Blood , — PubMed Abstract Google Scholar. Bianchi, M. Restoration of anti- Aspergillus defense by neutrophil extracellular traps in human chronic granulomatous disease after gene therapy is calprotectin-dependent.

Allergy Clin. Bos, C. Genetic analysis and the construction of master strains for assignment of genes to six linkage groups in Aspergillus niger. Bose, S. Polarity of human parainfluenza virus type 3 infection in polarized human lung epithelial A cells: role of microfilament and microtubule. Bowen, A. Induction of contour sensing in Aspergillus niger by stress and its relevance to fungal growth mechanics and hyphal tip structure. Fungal Genet. Braaksma, M. Goldman and S.

Google Scholar. Braem, S. Effective neutrophil phagocytosis of Aspergillus fumigatus is mediated by classical pathway complement activation.

Innate Immun. Brinkmann, V. Neutrophil extracellular traps kill bacteria. Science , — Brown, G. Innate antifungal immunity: the key role of phagocytes.

Bruns, S. Production of extracellular traps against Aspergillus fumigatus in vitro and in infected lung tissue is dependent on invading neutrophils and influenced by hydrophobin RodA.

PLoS Pathog. Bukhari, E. First case of extensive spinal cord infection with Aspergillus nidulans in a child with chronic granulomatous disease. Ctries 3, — Chai, L. Aspergillus fumigatus conidial melanin modulates host cytokine response. Immunobiology , — Chakrabarti, A. Invasive aspergillosis in developing countries. Cornillet, A. Comparison of epidemiological, clinical, and biological features of invasive aspergillosis in neutropenic and nonneutropenic patients: a 6-year survey.

Deak, E. Aspergillus terreus accessory conidia are unique in surface architecture, cell wall composition and germination kinetics. Eisenman, H. Synthesis and assembly of fungal melanin. Ellinger, I. Apical to basolateral transcytosis and apical recycling of immunoglobulin G in trophoblast-derived BeWo cells: effects of low temperature, nocodazole, and cytochalasin D.

Cell Res. Gugnani, H. Ecology and taxonomy of pathogenic aspergilli. Hall, L. Oxygen requirements of Aspergillus species. Hasenberg, M. Phagocyte responses towards Aspergillus fumigatus. Heinekamp, T. Aspergillus fumigatus melanins: interference with the host endocytosis pathway and impact on virulence. Henriet, S. Curtis, A. Finn, and A. Hope, W. Invasion of the alveolar-capillary barrier by Aspergillus spp.

Ibrahim-Granet, O. Phagocytosis and intracellular fate of Aspergillus fumigatus conidia in alveolar macrophages.

Jahn, B. Publication types Research Support, Non-U. Gov't Review. Sperschneider et al. In addition, Pierleoni et al. Note that sensitivity measures the fraction of true positive predictions while specificity measures the fraction of true negative predictions.

Supplementary Table S3 contains detailed annotations for secreted and cell membrane proteins in Aspergillus species. In the predicted secretomes of Aspergillus species, SSPs were defined as those with sequence length less than or equal to amino acid residues 21 , 98 , For each protein in Aspergillus species, the AAR value was computed following the method proposed by Gomez et al.

The AAR value of a given protein is computed by dividing the length of its amino acid sequence by the number of predicted antigenic regions. The average AAR value was computed for the set of secreted and cell membrane proteins, respectively, in each of the Aspergillus species considered here Fig.

To test whether the computed average AAR values for the set of secreted and cell membrane proteins, respectively, were significantly different from the average AAR value for the whole proteome of the same species, a p-value was computed by comparing against the average AAR values for equally-sized sets of randomly drawn proteins from the complete proteome of the organism. To test whether the average AAR value for the set of secreted proteins is significantly different from that of the set of cell membrane proteins of an Aspergillus species, Wilcoxon rank-sum test was performed to compare the two sets of different sizes Fig.

A microarray dataset for A. The microarray dataset from infected murine lungs 26 gave a reliable signal for genes in A. Gene expression data 26 for A. Thereafter, secreted and cell membrane proteins in A. To further ascertain the similarity between the filtered set of A. However, experimentally identified protein structures are not available for most of the filtered set of secreted and cell membrane proteins in A. Thus, good quality structure models of filtered proteins in A.

Filtered proteins in A. Molecular docking is a widely used computational approach in structure-based drug design which predicts with substantial accuracy the plausible binding poses and binding affinity of a ligand to the binding site in the target protein of interest Here we employ AutoDock Vina to perform rigid docking wherein the target protein of interest is kept rigid while the ligand is flexible. Firstly, three ligand binding pockets for each filtered protein in A.

The binding affinity results obtained by docking drugs to the protein pockets from AutoDock Vina were tabulated Table 2. We would like to note that the docking protocol implemented here is capable of predicting with substantial accuracy the plausible docked poses with their binding affinities reported against the ligand. However, the docking protocol and chosen software have their limitations such as the target protein is kept rigid during our computations and protein structure models are used whenever experimental structures for target proteins are unavailable.

All data generated or analyzed during this study is included in this article and its supplementary information. Patterson, T. Kauffman, Peter G. Pappas, Jack D. Dismukes — Springer New York, Paulussen, C. Ecology of aspergillosis: insights into the pathogenic potency of Aspergillus fumigatus and some other Aspergillus species. PubMed Article Google Scholar. Baddley, J. Patterns of susceptibility of Aspergillus isolates recovered from patients enrolled in the Transplant-Associated Infection Surveillance Network.

Journal of clinical microbiology 47 , — British journal of haematology , — Balajee, S. Aspergillus alabamensis, a new clinically relevant species in the section Terrei.

Eukaryotic Cell 8 , — Practice guidelines for the diagnosis and management of aspergillosis: update by the Infectious Diseases Society of America.

Clinical Infectious Diseases 63 , e1—e60 Lin, S. Aspergillosis case-fatality rate: systematic review of the literature. Perfect, J. In Molecular principles of fungal pathogenesis 3—11 American Society of Microbiology, Segal, B. Abad, A. What makes Aspergillus fumigatus a successful pathogen? Genes and molecules involved in invasive aspergillosis. Dagenais, T. Pathogenesis of Aspergillus fumigatus in invasive aspergillosis.

Clinical microbiology reviews 22 , — Kauffman, H. Protease-dependent activation of epithelial cells by fungal allergens leads to morphologic changes and cytokine production. J Allergy Clin Immunol , — Hohl, T. Aspergillus fumigatus: principles of pathogenesis and host defense.

Howard, S. Acquired antifungal drug resistance in Aspergillus fumigatus: epidemiology and detection. Chowdhary, A. Exploring azole antifungal drug resistance in Aspergillus fumigatus with special reference to resistance mechanisms. Choi, J. Fungal secretome database: integrated platform for annotation of fungal secretomes. Meinken, J. FunSecKB2: a fungal protein subcellular location knowledgebase.

Computational Molecular Biology 4 The UniProt, C. UniProt: the universal protein knowledgebase. Kim, K. Hacquard, S. A comprehensive analysis of genes encoding small secreted proteins identifies candidate effectors in Melampsora larici-populina poplar leaf rust.

Panstruga, R. Terrific protein traffic: the mystery of effector protein delivery by filamentous plant pathogens. Science , — Stergiopoulos, I. Fungal Effector Proteins. Gomez, S. Law, V. DrugBank 4. McDonagh, A. Sub-telomere directed gene expression during initiation of invasive aspergillosis. Adav, S. Proteomic analysis of temperature dependent extracellular proteins from Aspergillus fumigatus grown under solid-state culture condition.

Quantitative proteomic study of Aspergillus Fumigatus secretome revealed deamidation of secretory enzymes. Asif, A. Proteome of conidial surface associated proteins of Aspergillus fumigatus reflecting potential vaccine candidates and allergens. Champer, J. Farnell, E. Expression and secretion of Aspergillus fumigatus proteases are regulated in response to different protein substrates. A proteomics strategy to discover beta-glucosidases from Aspergillus fumigatus with two-dimensional page in-gel activity assay and tandem mass spectrometry.

Kumar, A. Identification of virulence factors and diagnostic markers using immunosecretome of Aspergillus fumigatus. Liu, D. Secretome diversity and quantitative analysis of cellulolytic Aspergillus fumigatus Z5 in the presence of different carbon sources.

Neustadt, M. Characterization and identification of proteases secreted by Aspergillus fumigatus using free flow electrophoresis and MS. Ouyang, H. Sharma Ghimire, P. Sharma, M. Evaluation of glycosyl hydrolases in the secretome of Aspergillus fumigatus and saccharification of alkali-treated rice straw. Singh, B. Immuno-reactive molecules identified from the secreted proteome of Aspergillus fumigatus.

Sriranganadane, D. Aspergillus protein degradation pathways with different secreted protease sets at neutral and acidic pH. Wartenberg, D.

Secretome analysis of Aspergillus fumigatus reveals Asp-hemolysin as a major secreted protein. Mellon, J. Aspergillus flavus-secreted proteins during an in vivo fungal-cotton carpel tissue interaction. Identification of hydrolytic activities expressed by Aspergillus flavus grown on cotton carpel tissue. Muthu Selvam, R. Data set for the mass spectrometry based exoproteome analysis of Aspergillus flavus isolates.

Selvam, R. Exoproteome of Aspergillus flavus corneal isolates and saprophytes: identification of proteoforms of an oversecreted alkaline protease. Proteomic analysis of the secretory response of Aspergillus niger to D-maltose and D-xylose. Transcriptome analysis of Aspergillus niger grown on sugarcane bagasse. Braaksma, M. An inventory of the Aspergillus niger secretome by combining in silico predictions with shotgun proteomics data.

Lu, X. The intra- and extracellular proteome of Aspergillus niger growing on defined medium with xylose or maltose as carbon substrate. Borin, G. Florencio, C.

Secretome data from Trichoderma reesei and Aspergillus niger cultivated in submerged and sequential fermentation methods.

Krijgsheld, P. Spatially resolving the secretome within the mycelium of the cell factory Aspergillus niger. Tsang, A. Analytical and computational approaches to define the Aspergillus niger secretome. Wang, L. Mapping N-linked glycosylation sites in the secretome and whole cells of Aspergillus niger using hydrazide chemistry and mass spectrometry.

Nitsche, B. The carbon starvation response of Aspergillus niger during submerged cultivation: insights from the transcriptome and secretome. Benoit-Gelber, I. Mixed colonies of Aspergillus niger and Aspergillus oryzae cooperatively degrading wheat bran. Couturier, M. Post-genomic analyses of fungal lignocellulosic biomass degradation reveal the unexpected potential of the plant pathogen Ustilago maydis. Han, M. Extracellular proteome of Aspergillus terreus grown on different carbon sources.

Do cultural conditions induce differential protein expression: Profiling of extracellular proteome of Aspergillus terreus CM Nekiunaite, L. Lytic polysaccharide monooxygenases and other oxidative enzymes are abundantly secreted by Aspergillus nidulans grown on different starches. Saykhedkar, S. A time course analysis of the extracellular proteome of Aspergillus nidulans growing on sorghum stover. However, those qualities that make A.

For, were it not for those features, the spectrum of those fungi causing invasive fungal infections would mirror that of air surveys What are some of the growth characteristics of this grass eater that allow it to be a successful opportunistic pathogen?

The reported growth rate of isolates of Aspergillus is often derived from measuring both the time required to germinate and the rate of apical extension of the hyphae. Germination initiates the asexual developmental program in the fungus.

When the resting conidia of A. The conidia undergo a period of isotropic growth before switching to a polar growth program and producing a germ tube These are the first steps in growth of a new fungal colony, whether it is in the compost heap or the lung of a host. Therefore, it is important that these steps be carried out quickly, efficiently and that a compost organism is able to undergo this developmental program at elevated temperature.

When conidia from clinical isolates of three Aspergillus species, A. Growth rate in filamentous fungi can be measured in a number of different ways, and the results from different methods don't always agree One way to measure the growth of a filamentous fungus is to measure the apical growth rate of hyphae as a function of colony diameter.

A specified number of conidia may be spotted into the center of a plate or a plug from a mature colony may be placed in the center of a plate 16— The biomass of the fungus can also be determined, either using absorbance or dry weight 16 , Using absorbance to measure growth in microtiter plates, different isolates of A.

This suggests that factors that promote faster growth rates in vitro may also contribute to the organism's ability to infect a host. Using dry weight to measure growth of an isogenic set of organism for the gene rasB , the mutant was shown to produce equivalent biomass to the wild type and reconstituted mutant strains, approximately 30 mg In this case the apical growth rate seemed a better predictor of in vivo results than did biomass.

But in the plant pathogen Trichoderma virens , a mutant in a MAP kinase, TmkA, had both reduced biomass and reduced ability to grow in plants To look more specifically at thermotolerant growth and virulence, the nucleolar protein CgrA, which plays a role in ribosome biogenesis, may be instructive But is there an upper temperature limit beyond which the ability to thrive no longer offers an increased in vivo advantage?

In the only study examining mutants of A. However, when tested in two different murine models of IA, no difference in virulence between the mutant and the wild type was seen. Since this is an unknown gene, all that can be concluded is that ThtA, although required for high temperature growth, is not required for in vivo growth and virulence. Since A. In the compost pile, A.

In this capacity, the organism must be able to respond to nutrient limitations, both qualitative and quantitative. This ability to sense carbon and nitrogen and to have the physiologic versatility to utilize different compounds contributes to the ability of A. A number of genes have been shown to be important in nitrogen utilization or to be regulated by nitrogen: rhbA , cpcA , areA , and sakA 24— In carbon utilization, the cAMP-dependent protein kinase PKA pathway is known to be regulated, in part, by glucose availability in Saccharomyces cerevisiae , as well as in A.

The third aspect upon which this discussion will touch is the effects of auxotrophies on virulence. The overall theme is that the fewer limitations there are on an organism's ability to obtain or manufacture nutrients, the more competitive it will be, regardless of the growth environment.

A second observation is that the availability of nutrients in an environment may not be obvious. Since the role played by nitrogen metabolism in pathogenicity of A. RhbA is a transcriptionally controlled ras homologue that is upstream of TOR in the TOR nutrient sensing and growth pathway 19 , 26 , As such, levels of RhbA message are increased in vitro following nitrogen starvation, but not carbon starvation, differentiating it from the mitogen-activated protein kinase SakA 26 , Mutants that lack rhbA show wild type growth on complex media or on minimal medium containing the good nitrogen source, ammonium tartrate, but they have reduced growth when nitrate, histidine or proline serve as the sole nitrogen source.

RhbA was first linked to virulence in A.