scholarly journals Development of a Ligand-Directed Approach To Study the Pathogenesis of Invasive Aspergillosis

2005 ◽  
Vol 73 (11) ◽  
pp. 7747-7758 ◽  
Author(s):  
Michail S. Lionakis ◽  
Johanna Lahdenranta ◽  
Jessica Sun ◽  
Wei Liu ◽  
Russell E. Lewis ◽  
...  
Keyword(s):  
Invasive Aspergillosis ◽  
Aspergillus Fumigatus ◽  
Invasive Pulmonary Aspergillosis ◽  
Phage Display Library ◽  
Therapeutic Interventions ◽  
Peptide Sequence ◽  
Formalin Fixed Paraffin ◽  
Formalin Fixed Paraffin Embedded ◽  
Immunosuppressed Patients ◽  
Binding Peptides

ABSTRACT Invasive aspergillosis is a leading cause of infectious death in immunosuppressed patients. Here, we adapted a phage display library-based selection to screen and identify binding peptides to the surface of Aspergillus fumigatus conidia and hyphae. We identified a peptide (sequence CGGRLGPFC) that reliably binds to the surface of Aspergillus fumigatus hyphae. Binding was not Aspergillus strain specific, as it was also observed in hyphae of other Aspergillus clinical isolates. Furthermore, CGGRLGPFC-displaying phage targets Aspergillus fumigatus hyphae on formalin-fixed paraffin-embedded histopathology sections of lung tissue recovered from mice with invasive pulmonary aspergillosis. This approach may yield reagents such as peptidomimetics for novel diagnostic and therapeutic interventions in invasive aspergillosis.

scholarly journals Chromatin profiling reveals genome stability heterogeneity in clinical isolates of the human pathogen Aspergillus fumigatus

2021 ◽  
Author(s):  
Ana Cristina Colabardini ◽  
Fang Wang ◽  
Zhengqiang Miao ◽  
Lakhansing Pardeshi ◽  
Clara Valero ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Genome Stability ◽  
Genome Instability ◽  
Invasive Pulmonary Aspergillosis ◽  
Biosynthetic Gene Cluster ◽  
Clinical Isolates ◽  
Immunosuppressed Patients ◽  
Life Threatening ◽  
Metabolites Production ◽  
Chromatin Profiling

Invasive Pulmonary aspergillosis is a life-threatening infection in immunosuppressed patients caused by the filamentous fungus Aspergillus fumigatus. Chromatin structure regulation is important for genome stability maintenance and has the potential to lead to genome rearrangements driving differences in virulence and pathogenesis of different A. fumigatus isolates. Here, we compared the chromatin activities of the most investigated clinical isolates Af293 and CEA17 and uncovered striking differences in the number, locations and expression of transposable elements. We found evidence for higher genome instability in Af293 as compared to CEA17 and identified a spontaneous Af293 variant that exhibits gross chromosomal alterations including the loss of a 320 kb long segment in chromosome VIII and the amplification of a biosynthetic gene cluster. As a consequence of these re-arrangements, the variant shows increased secondary metabolites production, growth and virulence. Our work emphasizes genome stability heterogeneity as an evolutionary driver of A. fumigatus fitness and virulence.

scholarly journals 2599. Studying the Effects of Altering Histone Modification on Aspergillus fumigatus Virulence

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S903-S903
Author(s):  
Pam Lee ◽  
Hong Liu ◽  
Scott Filler
Keyword(s):  
Invasive Aspergillosis ◽  
Aspergillus Fumigatus ◽  
Histone Modification ◽  
Histone Deacetylase ◽  
Cell Damage ◽  
Invasive Pulmonary Aspergillosis ◽  
Epithelial Cell Line ◽  
Saga Complex

Abstract Background As there are few drugs for treating invasive aspergillosis, there is an urgent need for new antifungal agents. Enzymes involved in histone modification are possible antifungal drug targets. We set out to investigate whether genes whose products are involved in histone modifications influence the virulence of Aspergillus fumigatus (Af). Methods Genes whose products were likely involved in histone modification were deleted in strain Af293 using CRISPR-Cas9. Virulence was assessed in a triamcinolone-treated mouse model of invasive pulmonary aspergillosis. The extent of Af-induced damage to the A549 pulmonary epithelial cell line was determined by Cr51 release assay. Results Af genes were selected for investigation based on their homology to genes encoding known histone modifying proteins and their high expression level in vivo. The genes were predicted to encode members of the COMPASS histone methyltransferase complex (cclA/bre2, set2/Afu5g06000), the SAGA histone acetyltransferase complex (spt3, spt8), and the RPDL histone deacetylase complex (hosA). The ΔcclA and Δset2 mutants had significant growth defects on rich media and were not tested further. The Δspt3 and Δspt8 mutants grew normally and had mild conidiation defects. The ΔhosA mutant had wild-type (WT) growth and conidiation in vitro. Mice infected with the WT strain had 100% mortality within 9 days whereas mice infected the Δspt3, Δspt8, and ΔhosA mutants had only 40% mortality by 21 days. The ΔhosA mutant also had impaired capacity to damage pulmonary epithelial cells in vitro. Conclusion Ccla and Set2, components of the COMPASS complex, are required for normal growth in vitro. Spt3 and Spt8, members of the SAGA complex, are required for normal conidiation and virulence. HosA, part of the RPD3L complex, is necessary for maximal virulence and induction of host cell damage. Our results suggest that the HosA histone deacetylase may be a promising drug target for treating invasive aspergillosis. Disclosures All authors: No reported disclosures.

scholarly journals Inhaled Voriconazole for Prevention of Invasive Pulmonary Aspergillosis

2009 ◽  
Vol 53 (6) ◽  
pp. 2613-2615 ◽  
Author(s):  
Justin A. Tolman ◽  
Nathan P. Wiederhold ◽  
Jason T. McConville ◽  
Laura K. Najvar ◽  
Rosie Bocanegra ◽  
...  
Keyword(s):  
Invasive Aspergillosis ◽  
Aspergillus Fumigatus ◽  
Amphotericin B ◽  
Murine Model ◽  
Invasive Pulmonary Aspergillosis ◽  
Invasive Disease ◽  
Pulmonary Aspergillosis ◽  
Drug Concentrations ◽  
Intravenous Formulation

ABSTRACT Targeted airway delivery of antifungals as prophylaxis against invasive aspergillosis may lead to high lung drug concentrations while avoiding toxicities associated with systemically administered agents. We evaluated the effectiveness of aerosolizing the intravenous formulation of voriconazole as prophylaxis against invasive pulmonary aspergillosis caused by Aspergillus fumigatus in an established murine model. Inhaled voriconazole significantly improved survival and limited the extent of invasive disease, as assessed by histopathology, compared to control and amphotericin B treatments.

scholarly journals Posaconazole Prophylaxis in Experimental Azole-Resistant Invasive Pulmonary Aspergillosis

2014 ◽  
Vol 59 (3) ◽  
pp. 1487-1494 ◽  
Author(s):  
Seyedmojtaba Seyedmousavi ◽  
Johan W. Mouton ◽  
Willem J. G. Melchers ◽  
Paul E. Verweij
Keyword(s):  
Invasive Aspergillosis ◽  
Aspergillus Fumigatus ◽  
Murine Model ◽  
Pulmonary Infection ◽  
Invasive Pulmonary Aspergillosis ◽  
Clinical Isolates ◽  
Wild Type ◽  
Breakthrough Infection ◽  
Pulmonary Aspergillosis ◽  
Content Type

ABSTRACTWe investigated the efficacy of posaconazole prophylaxis in preventing invasive aspergillosis due to azole-resistantAspergillus fumigatusisolates. Using a neutropenic murine model of pulmonary infection, posaconazole prophylaxis was evaluated using three isogenic clinical isolates, with posaconazole MICs of 0.063 mg/liter (wild type), 0.5 mg/liter (F219I mutation), and 16 mg/liter. A fourth isolate harboring TR34/L98H (MIC of 0.5 mg/liter) was also tested. Posaconazole prophylaxis was effective inA. fumigatuswith posaconazole MICs of ≤0.5 mg/liter, where 100% survival was reached. However, breakthrough infection was observed in mice infected with the isolate for which the posaconazole MIC was >16 mg/liter.

scholarly journals Chromatin profiling reveals heterogeneity in clinical isolates of the human pathogen Aspergillus fumigatus

PLoS Genetics ◽  
2022 ◽  
Vol 18 (1) ◽  
pp. e1010001
Author(s):  
Ana Cristina Colabardini ◽  
Fang Wang ◽  
Zhengqiang Miao ◽  
Lakhansing Pardeshi ◽  
Clara Valero ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Genome Stability ◽  
Invasive Pulmonary Aspergillosis ◽  
Clinical Isolates ◽  
Dna Repeats ◽  
Immunosuppressed Patients ◽  
Chromosomal Changes ◽  
Metabolites Production ◽  
Chromatin Profiling ◽  
Genome Heterogeneity

Invasive Pulmonary Aspergillosis, which is caused by the filamentous fungus Aspergillus fumigatus, is a life-threatening infection for immunosuppressed patients. Chromatin structure regulation is important for genome stability maintenance and has the potential to drive genome rearrangements and affect virulence and pathogenesis of pathogens. Here, we performed the first A. fumigatus global chromatin profiling of two histone modifications, H3K4me3 and H3K9me3, focusing on the two most investigated A. fumigatus clinical isolates, Af293 and CEA17. In eukaryotes, H3K4me3 is associated with active transcription, while H3K9me3 often marks silent genes, DNA repeats, and transposons. We found that H3K4me3 deposition is similar between the two isolates, while H3K9me3 is more variable and does not always represent transcriptional silencing. Our work uncovered striking differences in the number, locations, and expression of transposable elements between Af293 and CEA17, and the differences are correlated with H3K9me3 modifications and higher genomic variations among strains of Af293 background. Moreover, we further showed that the Af293 strains from different laboratories actually differ in their genome contents and found a frequently lost region in chromosome VIII. For one such Af293 variant, we identified the chromosomal changes and demonstrated their impacts on its secondary metabolites production, growth and virulence. Overall, our findings not only emphasize the influence of genome heterogeneity on A. fumigatus fitness, but also caution about unnoticed chromosomal variations among common laboratory strains.

Sequencing Analysis and Phylogenetic Tree of HPV Isolated from Breast Cancer Patients at Thi-Qar Province/Iraq

2020 ◽  
pp. 37-40
Keyword(s):  
Nucleotide Sequence ◽  
Phylogenetic Tree ◽  
Evolutionary Relationship ◽  
Nucleotide Sequencing ◽  
Sequencing Analysis ◽  
Breast Cancer Patients ◽  
The North ◽  
Formalin Fixed Paraffin ◽  
Formalin Fixed Paraffin Embedded ◽  
History Of

Genetic variety examination has demonstrated fundamental to the understanding of the epidemiological and developmental history of Papillomavirus (HPV), for the development of accurate diagnostic tests and for efficient vaccine design. The HPV nucleotide diversity has been investigated widely among high-risk HPV types. To make the nucleotide sequence of HPV and do the virus database in Thi-Qar province, and compare sequences of our isolates with previously described isolates from around the world and then draw its phylogenetic tree, this study done. A total of 6 breast formalin-fixed paraffin-embedded (FFPE) of the female patients were included in the study, divided as 4 FFPE malignant tumor and 2 FFPE of benign tumor. The PCR technique was implemented to detect the presence of HPV in breast tissue, and the real-time PCR used to determinant HPV genotypes, then determined a complete nucleotide sequence of HPV of L1 capsid gene, and draw its phylogenetic tree. The nucleotide sequencing finding detects a number of substitution mutation (SNPs) in (L1) gene, which have not been designated before, were identified once in this study population, and revealed that the HPV16 strains have the evolutionary relationship with the South African race, while, the HPV33 and HPV6 showing the evolutionary association with the North American and East Asian race, respectively.

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