Abstract:
:Aspergillosis associated with azole-resistant Aspergillus fumigatus has a mortality rate that can approach 90% in certain patient populations. The best-understood avenue for azole resistance involves changes in the cyp51A gene that encodes the target of azole drugs, lanosterol α-14 demethylase. The most common azole resistance allele currently described is a linked change corresponding to a change in the coding sequence of cyp51A and a duplication of a 34-bp region in the promoter leading to a tandem repeat (TR). Our previous studies identified a positively acting transcription factor called AtrR that binds to the promoter of cyp51A as well as that of an important membrane transporter protein gene called abcG1 In this work, we characterize two different mutant alleles of atrR, either an overproducing or an epitope-tagged form, causing constitutive activation of this factor. Using an epitope-tagged allele of atrR for chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq), the genomic binding sites for AtrR were determined. Close to 900 genes were found to have an AtrR response element (ATRE) in their promoter regions. Transcriptome evaluation by RNA sequencing (RNA-seq) indicated that both alleles led to elevated transcription of a subset of target genes. An electrophoretic mobility shift assay and DNase I protection mapping localized the ATREs in both the abcG1 and cyp51A promoters. The ATRE in cyp51A was located within the 34-bp repeat element. Virulence in a murine model was compromised when AtrR was either deleted or overproduced, indicating that the proper dosage of this factor is key for pathogenesis.IMPORTANCEAspergillus fumigatus is the major filamentous fungal pathogen in humans. Infections associated with A. fumigatus are often treated with azole drugs, but resistance to these antifungal agents is increasing. Mortality from aspergillosis associated with azole-resistant fungi is extremely high. Previous work has identified transcriptional control of the azole drug target-encoding gene cyp51A as an important contributor to resistance in A. fumigatus Here, we demonstrate that the transcription factor AtrR binds to a region in the cyp51A promoter that is associated with alleles of this gene conferring clinically important azole resistance. Using high-throughput genomic technologies, we also uncover a large suite of target genes controlled by AtrR. These data indicate that AtrR coordinately regulates many different processes involved in drug resistance, metabolism, and virulence. Our new understanding of AtrR function provides important new insight into the pathogenesis of A. fumigatus.
journal_name
mBiojournal_title
mBioauthors
Paul S,Stamnes M,Thomas GH,Liu H,Hagiwara D,Gomi K,Filler SG,Moye-Rowley WSdoi
10.1128/mBio.02563-18subject
Has Abstractpub_date
2019-03-12 00:00:00issue
2issn
2150-7511pii
mBio.02563-18journal_volume
10pub_type
杂志文章相关文献
mBio文献大全abstract::The pathogenic species of Cryptococcus are a major cause of mortality owing to severe infections in immunocompromised as well as immunocompetent individuals. Although antifungal treatment is usually effective, many patients relapse after treatment, and in such cases, comparative analyses of the genomes of incident and...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.00166-17
更新日期:2017-03-07 00:00:00
abstract::Malaria parasites increase their host erythrocyte's permeability to various nutrients, fueling intracellular pathogen development and replication. The plasmodial surface anion channel (PSAC) mediates this uptake and is linked to the parasite-encoded RhopH complex, consisting of CLAG3, RhopH2, and RhopH3. While interac...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.01354-20
更新日期:2020-09-08 00:00:00
abstract::To address the question of how microbial diversity and function in the oral cavities of children relates to caries diagnosis, we surveyed the supragingival plaque biofilm microbiome in 44 juvenile twin pairs. Using shotgun sequencing, we constructed a genome encyclopedia describing the core supragingival plaque microb...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.01631-18
更新日期:2018-11-27 00:00:00
abstract::Candida albicans has developmental programs that govern transitions between yeast and filamentous morphologies and between unattached and biofilm lifestyles. Here, we report that filamentation, intercellular adherence, and biofilm development were inhibited during interactions between Candida albicans and Pseudomonas ...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.00526-12
更新日期:2013-01-29 00:00:00
abstract:UNLABELLED:Small colony variants (SCVs) are naturally occurring subpopulations of bacteria. The clinical characteristics and treatment outcomes of patients with prosthetic joint infection (PJI) caused by staphylococcal SCVs are unknown. This study was a retrospective series of 113 patients with staphylococcal PJI, with...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.01910-14
更新日期:2014-09-30 00:00:00
abstract:UNLABELLED:A change in viral hemagglutinin (HA) receptor binding specificity from α2,3- to α2,6-linked sialic acid is necessary for highly pathogenic avian influenza (AI) virus subtype H5N1 to become pandemic. However, details of the human-adaptive change in the H5N1 virus remain unknown. Our database search of H5N1 cl...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.00081-15
更新日期:2015-04-07 00:00:00
abstract::A simple method for filtering water to reduce the incidence of cholera was tested in a field trial in Matlab, Bangladesh, and proved effective. A follow-up study was conducted 5 years later to determine whether the filtration method continued to be employed by villagers and its impact on the incidence of cholera. A to...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.00034-10
更新日期:2010-05-18 00:00:00
abstract:UNLABELLED:β-Lactam antibiotics are the drugs of choice to treat pneumococcal infections. The spread of β-lactam-resistant pneumococci is a major concern in choosing an effective therapy for patients. Systematically tracking β-lactam resistance could benefit disease surveillance. Here we developed a classification syst...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.00756-16
更新日期:2016-06-14 00:00:00
abstract::During DNA replication, stalling can occur when the replicative DNA polymerases encounter lesions or hard-to replicate regions. Under these circumstances, the processivity factor PCNA gets ubiquitylated at lysine 164, inducing the DNA damage tolerance (DDT) mechanisms that can bypass lesions encountered during DNA rep...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.00705-20
更新日期:2020-05-05 00:00:00
abstract::Hepatitis E virus (HEV), a single-strand positive-sense RNA virus, is an understudied but important human pathogen. The virus can establish infection at a number of host tissues, including the small intestine and liver, causing acute and chronic hepatitis E as well as certain neurological disorders. The retinoic acid-...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.03103-19
更新日期:2020-01-14 00:00:00
abstract::Flavor production in yeast fermentation is of paramount importance for industrial production of alcoholic beverages. Although major enzymes of flavor compound biosynthesis have been identified, few specific mutations responsible for strain diversity in flavor production are known. The ATF1-encoded alcohol acetyl coenz...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.01279-18
更新日期:2018-08-28 00:00:00
abstract:UNLABELLED:Recent studies strongly suggest that the gene expression sustaining both normal and pathogenic bacterial growth is governed by the structural dynamics of the chromosome. However, the mechanistic device coordinating the chromosomal configuration with selective expression of the adaptive traits remains largely...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.00353-15
更新日期:2015-04-28 00:00:00
abstract::Cryptococcus neoformans is the main etiologic agent of cryptococcal meningitis and causes a significant number of deadly infections per year. Although it is well appreciated that host immune responses are crucial for defense against cryptococcosis, our understanding of factors that control the development of effective...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.01828-17
更新日期:2018-01-09 00:00:00
abstract::In bacteria, elongation factor Tu is a translational cofactor that forms ternary complexes with aminoacyl-tRNA (aa-tRNA) and GTP. Binding of a ternary complex to one of four flexible L7/L12 units on the ribosome tethers a charged tRNA in close proximity to the ribosomal A site. Two sequential tests for a match between...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.02143-17
更新日期:2018-01-16 00:00:00
abstract:UNLABELLED:Middle East respiratory syndrome coronavirus (MERS-CoV) is the first highly pathogenic human coronavirus to emerge since severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002. Like many coronaviruses, MERS-CoV carries genes that encode multiple accessory proteins that are not required for replicat...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.00258-16
更新日期:2016-03-29 00:00:00
abstract::Fungal cell wall mannans are complex carbohydrate polysaccharides with different structures in yeasts and molds. In contrast to yeasts, their biosynthetic pathway has been poorly investigated in filamentous fungi. In Aspergillus fumigatus, the major mannan structure is a galactomannan that is cross-linked to the β-1,3...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.02647-18
更新日期:2019-02-12 00:00:00
abstract::The USA300 North American epidemic (USA300-NAE) clone of methicillin-resistant Staphylococcus aureus has caused a wave of severe skin and soft tissue infections in the United States since it emerged in the early 2000s, but its geographic origin is obscure. Here we use the population genomic signatures expected from th...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.02016-17
更新日期:2018-01-02 00:00:00
abstract::Bordetella pertussis controls the expression of its virulence regulon through the two-component system BvgAS. BvgS is a prototype for a family of multidomain sensor kinases. In BvgS, helical linkers connect periplasmic Venus flytrap (VFT) perception domains to a cytoplasmic Per-Arnt-Sim (PAS) domain and the PAS domain...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.02052-17
更新日期:2018-02-27 00:00:00
abstract:UNLABELLED:Conjugate vaccines are known to be one of the most effective and safest types of vaccines against bacterial pathogens. Previously, vaccine biosynthesis has been performed by using N-linked glycosylation systems. However, the structural specificity of these systems for sugar substrates has hindered their appl...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.00443-16
更新日期:2016-04-26 00:00:00
abstract:UNLABELLED:Clostridium perfringens enterotoxin (CPE) contributes to several important human gastrointestinal (GI) diseases. This toxin and its derivatives are also being explored for translational applications, i.e., cancer therapy or drug delivery. Some, but not all, members of the 24-member claudin (Cldn) family of m...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.00594-12
更新日期:2013-01-15 00:00:00
abstract::Enterohemorrhagic Escherichia coli (EHEC) is a major cause of foodborne gastrointestinal illness. EHEC uses a specialized type III secretion system (T3SS) to form attaching and effacing lesions in the colonic epithelium and outcompete commensal gut microbiota to cause disease. A recent report in mBio (E. A. Cameron, M...
journal_title:mBio
pub_type: 评论,杂志文章
doi:10.1128/mBio.00115-19
更新日期:2019-02-26 00:00:00
abstract:UNLABELLED:The group of proteins known as serine protease autotransporters of Enterobacteriaceae (SPATE) is a growing family of serine proteases secreted to the external milieu by the type V secretion system. Pet toxin and some other SPATE belong to the class 1 cytotoxic SPATE, which have comparable protease strength o...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.00838-13
更新日期:2013-12-10 00:00:00
abstract::Chlamydiales species are obligate intracellular bacteria lacking a classical peptidoglycan sacculus but relying on peptidoglycan synthesis for cytokinesis. While septal peptidoglycan biosynthesis seems to be regulated by MreB actin and its membrane anchor RodZ rather than FtsZ tubulin in Chlamydiales, the mechanism of...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.01128-19
更新日期:2019-07-16 00:00:00
abstract:UNLABELLED:Methicillin-resistant Staphylococcus aureus (MRSA) strains are leading causes of hospital-acquired infections in the United States, and clonal cluster 5 (CC5) is the predominant lineage responsible for these infections. Since 2002, there have been 12 cases of vancomycin-resistant S. aureus (VRSA) infection i...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.00112-12
更新日期:2012-05-22 00:00:00
abstract::5-Aminosalicylic acid (5-ASA), a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist, is a widely used first-line medication for the treatment of ulcerative colitis, but its anti-inflammatory mechanism is not fully resolved. Here, we show that 5-ASA ameliorates colitis in dextran sulfate sodium (DSS)-tre...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.03227-20
更新日期:2021-01-19 00:00:00
abstract::The β-barrel assembly machinery, the Bam complex, is central to the biogenesis of integral outer membrane proteins (OMPs) as well as OMP-dependent surface-exposed lipoproteins, such as regulator of capsule synthesis protein F (RcsF). Previous genetic analysis established the model that nonessential components BamE and...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.00660-19
更新日期:2019-05-21 00:00:00
abstract::Nullbasic is a mutant form of the HIV-1 transcriptional activator protein (Tat) that strongly inhibits HIV-1 transcription and replication in lymphocytes in vitro To investigate Nullbasic inhibition in vivo, we employed an NSG mouse model where animals were engrafted with primary human CD4+ cells expressing a Nullbasi...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.01769-19
更新日期:2019-08-27 00:00:00
abstract:UNLABELLED:Marine methane seeps are globally distributed geologic features in which reduced fluids, including methane, are advected upward from the subsurface. As a result of alkalinity generation during sulfate-coupled methane oxidation, authigenic carbonates form slabs, nodules, and extensive pavements. These carbona...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.01348-15
更新日期:2015-12-22 00:00:00
abstract::Posttranslational modification of a protein, either alone or in combination with other modifications, can control properties of that protein, such as enzymatic activity, localization, stability, or interactions with other molecules. N-ε-Lysine acetylation is one such modification that has gained attention in recent ye...
journal_title:mBio
pub_type: 杂志文章,评审
doi:10.1128/mBio.02708-18
更新日期:2019-04-09 00:00:00
abstract::Methicillin-resistant Staphylococcus aureus (MRSA) resists nearly all β-lactam antibiotics that have a bactericidal activity. However, whether the empirically used β-lactams enhance MRSA pathogenicity in vivo remains unclear. In this study, we showed that a cluster of lipoprotein-like genes (lpl, sa2275 to sa2273 [sa2...
journal_title:mBio
pub_type: 杂志文章
doi:10.1128/mBio.00880-19
更新日期:2019-06-11 00:00:00