Gene Expression Profiling of Polymorphonuclear Leukocytes Treated with the Culture Filtrate of <i>Aspergillus fumigatus</i> and Gliotoxin

Higurashi, Hiromi; Arai, Makoto; Watanabe, Akira; Igari, Hidetoshi; Seki, Naohiko; Kamei, Katsuhiko; Kuriyama, Takayuki

doi:10.1111/j.1348-0421.2007.tb03928.x

Cited by 11 publications

(5 citation statements)

References 40 publications

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“…Studies have found that remnant A. fumigatus can be transformed from conidia to mycelium form within PMNs, suggesting an important role for PMNs in mycelium removal. This model has been supported by other studies wherein cultured diffusates of A. fumigatus (AfDs) were shown to have immunosuppressive effects on PMNs (Higurashi et al, 2007). Previous studies have elucidated an indispensable role for PMNs in the clearance of A. fumigatus (Ikegami et al, 1998).…”

Section: Introductionsupporting

confidence: 68%

Aspergillus fumigatus diffusates suppress polymorphonuclear neutrophil phagocytic functions and respiratory burst levels in hematopoietic stem cell transplantation patients

Xh¹,

Yc²,

By³

et al. 2015

Genet. Mol. Res.

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ABSTRACT. Invasive aspergillosis (IA) is a severe infection that commonly occurs in immunocompromised patients after hematopoietic stem cell transplantation (HSCT). The present study explores the effect of Aspergillus fumigatus diffusates (AfDs) on phagocytic function and superoxide anion (O 2 − ) burst levels in polymorphonuclear neutrophils (PMNs) from post-HSCT patients. A. fumigatus conidia with or without AfD were used to stimulate the PMN from healthy donor or HSCT patient for two hours. PMN morphology was visualized by scanning electron microscopy. The levels of respiratory burst O 2 − produced by the PMNs were determined by flow cytometry. PMN phagocytic rates and phagocytic indexes were observed and calculated using periodic acid-Schiff (PAS) staining under a light-field microscope. No difference X.H. Chen et al. 9234©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 14 (3): 9233-9243 (2015) was found between the PMN phagocytic rates, phagocytic indexes, or O 2 − respiratory burst levels in health donor PMNs following treatments of A. fumigatus conidia with or without AfD. However, significant inhibition of these indices was seen in the PMNs from HSCT patients following treatment of A. fumigatus conidia plus AfD, compared to that with conidium treatment alone (P < 0.05). Therefore, AfD significantly inhibited the phagocytic function of PMNs from HSCT patients, potentially through inhibition of intracellular respiratory burst levels during phagocytosis. This suggests that the reason underlying the greater susceptibility of HSCT patients to aspergillosis might be the existence of AfD in vivo during infection. Further research on the mechanisms by which AfD affects the phagocytic function of PMNs from HSCT patients is therefore of great significance for the prevention of IA.

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Section: Introductionsupporting

confidence: 68%

Aspergillus fumigatus diffusates suppress polymorphonuclear neutrophil phagocytic functions and respiratory burst levels in hematopoietic stem cell transplantation patients

Xh¹,

Yc²,

By³

et al. 2015

Genet. Mol. Res.

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“…Most studies on the mechanisms of GT action have focused on its proapoptotic effects in mammalian cells (7). Nonetheless, a recent gene expression profiling study of human polymorphonuclear neutrophils exposed to GT demonstrated broad-spectrum changes on the host transcriptosome (8). In addition to its direct immunosuppressive properties, GT also affects other important cellular functions, such as actin cytoskeleton organization (3).…”

Section: Discussionmentioning

confidence: 99%

Genomewide Screening for Genes Associated with Gliotoxin Resistance and Sensitivity in Saccharomyces cerevisiae

Chamilos

Lewis

Lamaris

et al. 2008

Antimicrob Agents Chemother

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Gliotoxin (GT) is a secondary fungal metabolite with pleiotropic immunosuppressive properties that have been implicated in Aspergillus virulence. However, the mechanisms of GT cytotoxicity and its molecular targets in eukaryotic cells have not been fully characterized. We screened a haploid library of Saccharomyces cerevisiae single-gene deletion mutants (4,787 strains in EUROSCARF) to identify nonessential genes associated with GT increased resistance (GT-IR) and increased sensitivity (GT-IS). The susceptibility of the wild-type parental strain BY4741 to GT was initially assessed by broth microdilution methods using different media. GT-IR and GT-IS were defined as a fourfold increase and decrease, respectively, in MIC, and this was additionally confirmed by susceptibility testing on agar yeast extract-peptone-glucose plates. The specificity of GT-IR and GT-IS mutants exhibiting normal growth compared with the wild-type strain was further tested in studies of their susceptibility to conventional antifungal agents, cycloheximide, and H 2 O 2 . GT-IR was associated with the disruption of genes acting in general metabolism (OPI1, SNF1, IFA38), mitochondrial function (RTG2), DNA damage repair (RAD18), and vesicular transport (APL2) and genes of unknown function (YGL235W, YOR345C, YLR456W, YGL072C). The disruption of three genes encoding transsulfuration (CYS3), mitochondrial function (MEF2), and an unknown function (YKL037W) led to GT-IS. Specificity for GT-IR and GT-IS was observed in all mutants. Importantly, the majority (69%) of genes implicated in GT-IR (6/10) and GT-IS (2/3) have human homologs. We identified novel Saccharomyces genes specifically implicated in GT-IR or GT-IS. Because most of these genes are evolutionarily conserved, further characterization of their function could improve our understanding of GT cytotoxicity mechanisms in humans.

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“…In addition, CDC42 induces phagocytosis in macrophages via FcγR [ 34 ]. A study using human polymorphonuclear leukocyte (PMNs) showed that BCAR3 was down-regulated by gliotoxin, a mycotoxin produced by A. fumigatus , which further enhances the importance of this gene in the host immune response during fungal infection [ 35 ]. Early Growth Response 2 (EGR2) is a transcription factor closely related to HOXA4 gene and has been shown to be up-regulated during C. albicans infection in bone marrow derived macrophages [ 36 ].…”

Section: Resultsmentioning

confidence: 99%

Fungal biomarker discovery by integration of classifiers

et al. 2017

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BackgroundThe human immune system is responsible for protecting the host from infection. However, in immunocompromised individuals the risk of infection increases substantially with possible drastic consequences. In extreme, systemic infection can lead to sepsis which is responsible for innumerous deaths worldwide. Amongst its causes are infections by bacteria and fungi. To increase survival, it is mandatory to identify the type of infection rapidly. Discriminating between fungal and bacterial pathogens is key to determine if antifungals or antibiotics should be administered, respectively. For this, in situ experiments have been performed to determine regulation mechanisms of the human immune system to identify biomarkers. However, these studies led to heterogeneous results either due different laboratory settings, pathogen strains, cell types and tissues, as well as the time of sample extraction, to name a few.MethodsTo generate a gene signature capable of discriminating between fungal and bacterial infected samples, we employed Mixed Integer Linear Programming (MILP) based classifiers on several datasets comprised of the above mentioned pathogens.ResultsWhen combining the classifiers by a joint optimization we could increase the consistency of the biomarker gene list independently of the experimental setup. An increase in pairwise overlap (the number of genes that overlap in each cross-validation) of 43% was obtained by this approach when compared to that of single classifiers. The refined gene list was composed of 19 genes and ranked according to consistency in expression (up- or down-regulated) and most of them were linked either directly or indirectly to the ERK-MAPK signalling pathway, which has been shown to play a key role in the immune response to infection. Testing of the identified 12 genes on an unseen dataset yielded an average accuracy of 83%.ConclusionsIn conclusion, our method allowed the combination of independent classifiers and increased consistency and reliability of the generated gene signatures.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-017-4006-x) contains supplementary material, which is available to authorized users.

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Gene Expression Profiling of Polymorphonuclear Leukocytes Treated with the Culture Filtrate of Aspergillus fumigatus and Gliotoxin

Cited by 11 publications

References 40 publications

Aspergillus fumigatus diffusates suppress polymorphonuclear neutrophil phagocytic functions and respiratory burst levels in hematopoietic stem cell transplantation patients

Aspergillus fumigatus diffusates suppress polymorphonuclear neutrophil phagocytic functions and respiratory burst levels in hematopoietic stem cell transplantation patients

Genomewide Screening for Genes Associated with Gliotoxin Resistance and Sensitivity in Saccharomyces cerevisiae

Fungal biomarker discovery by integration of classifiers

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