Virulence Factor Of Aspergillus Fumigatus Research Articles

Effects Of Some Fungal Secondary Metabolite Against Some Cancer Cell Line

The promising feature of the fungi from the marine environment as a source for anticancer agents belongs to the fungal ability to produce several compounds and enzymes which contribute effectively against the cancer cells growth. Moreover, the compounds produced during the secondary metabolic process acts by changing the cell morphology and DNA fragmentation leading to apoptosis of the cancer cells. When compared to the other chemicals in the investigation, gliotoxin demonstrated the most cytotoxic effect. These findings suggest that gliotoxin could be a potential virulence factor of Aspergillus fumigatus during infection. Anti Cancer, the dreadful disease that spreads throughout the body, bringing its cells closer to death than life expectancy, will be defeated or at least slowed by natural plants. Many researchers and clinicians are familiar with the treatment of numerous plants, such as Rheum ribes. Cancer studies have shown that the usage of some medicinal herbs can help to minimize the severity of this dreadful disease, and plant care is also well understood. Bangladesh Journal of Medical Science Vol.22 (Special Issue) 2023 p.133-137

Gliotoxin from Aspergillus fumigatus Abrogates Leukotriene B4 Formation through Inhibition of Leukotriene A4 Hydrolase

The epidithiodioxopiperazine gliotoxin is a virulence factor of Aspergillus fumigatus, the most important airborne fungal pathogen of humans. Gliotoxin suppresses innate immunity in invasive aspergillosis, particularly by compromising neutrophils, but the underlying molecular mechanisms remain elusive. Neutrophils are the first responders among innate immune cells recruited to sites of infection by the chemoattractant leukotriene (LT)B4 that is biosynthesized by 5-lipoxygenase and LTA4 hydrolase (LTA4H). Here, we identified gliotoxin as inhibitor of LTA4H that selectively abrogates LTB4 formation in human leukocytes and in distinct animal models. Gliotoxin failed to inhibit the formation of other eicosanoids and the aminopeptidase activity of the bifunctional LTA4H. Suppression of LTB4 formation by gliotoxin required the cellular environment and/or reducing conditions, and only the reduced form of gliotoxin inhibited LTA4H activity. Conclusively, gliotoxin suppresses the biosynthesis of the potent neutrophil chemoattractant LTB4 by direct interference with LTA4H thereby impairing neutrophil functions in invasive aspergillosis.

GliA in Aspergillus fumigatus is required for its tolerance to gliotoxin and affects the amount of extracellular and intracellular gliotoxin

Gliotoxin is an important virulence factor of Aspergillus fumigatus. Although GliA putatively belongs to the major facilitator superfamily in the gliotoxin biosynthesis cluster, its roles remain unclear. To determine the function of GliA, we disrupted gliA in A. fumigatus. gliA disruption increased the susceptibility of A. fumigatus to gliotoxin. The gliT and gliA double-disrupted mutant had even higher susceptibility to gliotoxin than each individual disruptant. The extracellular release of gliotoxin was greatly decreased in the gliA disruptant. Mice infected with the gliA disruptant of A. fumigatus showed higher survival rates than those infected with the parent strain. These results strongly indicate that GliA, in addition to GliT, plays a significant role in the tolerance to gliotoxin and protection from extracellular gliotoxin in A. fumigatus by exporting the toxin. This also allows the fungus to evade the harmful effect of its own gliotoxin production. Moreover, GliA contributes to the virulence of A. fumigatus through gliotoxin secretion.

Gliotoxin Is a Virulence Factor of Aspergillus fumigatus : gliP Deletion Attenuates Virulence in Mice Immunosuppressed with Hydrocortisone

Gliotoxin is an immunosuppressive mycotoxin long suspected to be a potential virulence factor of Aspergillus fumigatus. Recent studies using mutants lacking gliotoxin production, however, suggested that the mycotoxin is not important for pathogenesis of A. fumigatus in neutropenic mice resulting from treatment with cyclophosphomide and hydrocortisone. In this study, we report on the pathobiological role of gliotoxin in two different mouse strains, 129/Sv and BALB/c, that were immunosuppressed by hydrocortisone alone to avoid neutropenia. These strains of mice were infected using the isogenic set of a wild type strain (B-5233) and its mutant strain (gliPDelta) and the the glip reconstituted strain (gliP(R)). The gliP gene encodes a nonribosomal peptide synthase that catalyzes the first step in gliotoxin biosynthesis. The gliPDelta strain was significantly less virulent than strain B-5233 or gliP(R) in both mouse models. In vitro assays with culture filtrates (CFs) of B-5233, gliPDelta, and gliP(R) strains showed the following: (i) deletion of gliP abrogated gliotoxin production, as determined by high-performance liquid chromatography analysis; (ii) unlike the CFs from strains B-5233 and gliP(R), gliPDelta CFs failed to induce proapoptotic processes in EL4 thymoma cells, as tested by Bak conformational change, mitochondrial-membrane potential disruption, superoxide production, caspase 3 activation, and phosphatidylserine translocation. Furthermore, superoxide production in human neutrophils was strongly inhibited by CFs from strain B-5233 and the gliP(R) strain, but not the gliPDelta strain. Our study confirms that gliotoxin is an important virulence determinant of A. fumigatus and that the type of immunosuppression regimen used is important to reveal the pathogenic potential of gliotoxin.

Effect of ostreolysin, an Asp-hemolysin isoform, on human chondrocytes and osteoblasts, and possible role of Asp-hemolysin in pathogenesis

Aspergillus fumigatus, a pathogenic mould causing a wide range of diseases including aspergillosis, produces a series of toxic substances which appear to act in an additive and/or synergic way on cells. Aspergillosis generally occurs in immunocompromised hosts or is associated with organ transplantation. From the muscul skeleton system the vertebrae, ribs and orbit are the most commonly affected, while the joints are less frequent targets. The cytolytic protein Asp-hemolysin is one of the toxins produced by Aspergillus fumigatus during infection. It belongs to the aegerolysin protein family and shares 43% identity in amino acid sequence with ostreolysin, a cytolysin from the mushroom Pleurotus ostreatus. In this work, ostreolysin was used in an experimental model to study the in vitro effects of aegerolysin-like proteins on human chondrocytes and osteoblasts. Immunostaining analyses showed selective binding and clustering of the protein on chondrocyte membranes, pointing to its association with distinctive membrane microdomains. Consequently, ostreolysin can induce effective permeabilization of both chondrocytes and osteoblasts. Based on sequence similarities of ostreolysin and Asp-hemolysin, their comparable cytolytic effects towards different cells, and similar signs of intoxication in experimental animals, our results indicate that Asp-hemolysin might be considered as a possible virulence factor of Aspergillus fumigatus during the infection of bone and cartilage.

A transformant of Aspergillus fumigatus deficient in the antigenic cytotoxin ASPFI.

The aspfI gene encoding a ribonucleotoxin, a putative virulence factor of Aspergillus fumigatus, was inactivated by gene disruption. Gene replacement through homologous recombination by the disrupted allele tagged by the hygromycin B resistance marker was performed by transformation of a pathogenic strain. One transformant with the disrupted aspfI gene failed to produce the ASPFI protein and was shown to be pathogenic for mice. We concluded that this ribotoxin is not a main factor in the colonization of the lung tissues by A. fumigatus.

Virulence of alkaline protease-deficient mutants of Aspergillus fumigatus.

The gene encoding the secreted alkaline protease, a suspected virulence factor of Aspergillus fumigatus, was inactivated by gene disruption. The disruption was performed by transformation of a pathogenic strain of the fungus with a linear DNA fragment carrying the gene from which the central part was replaced by the selectable Escherichia coli hygromycin B dominant resistance marker. Two transformants were shown to produce no alkaline protease. Restriction fragment analysis of the DNA of these two transformants was consistent for chromosomal integration of the disrupted gene by homologous recombination. Both isogenic alkaline protease-producing and non-producing A. fumigatus strains invaded lung tissues, causing comparable mortality in immunosuppressed mice. A significant residual proteolytic activity observed in alkaline protease non-producing strain cultures could play a role in the invasion of the tissues by the fungus.