Dynamics of interaction and internalisation of the antifungal protein PeAfpA into Penicillium digitatum morphotypes.

Antifungal proteins (AFPs) as the highly active PeAfpA from Penicillium expansum or PdAfpB from Penicillium digitatum exert promising antifungal activity, but their mode of action is not fully understood. We characterised the interaction of PeAfpA against P. digitatum, comparing it to the less active PdAfpB.

Epithelial uptake leads to fungal killing and is aberrant in COPD-derived epithelial cells.

Hundreds of spores of are inhaled daily by human beings, representing a constant, possibly fatal, threat to respiratory health. The small size of spores suggests that interactions with alveolar epithelial cells (AECs) are frequent; thus, we hypothesized that spore uptake by AECs is important for driving fungal killing and susceptibility to -related disease. Using single-cell approaches to measure spore uptake and its outcomes , we demonstrate that spores are internalized and killed by AECs during whole-animal infection.

Inferring fungal growth rates from optical density data.

Quantifying fungal growth underpins our ability to effectively treat severe fungal infections. Current methods quantify fungal growth rates from time-course morphology-specific data, such as hyphal length data. However, automated large-scale collection of such data lies beyond the scope of most clinical microbiology laboratories.

Conserved and Divergent Features of pH Sensing in Major Fungal Pathogens.

Purpose Of Review: For human fungal pathogens, sensory perception of extracellular pH is essential for colonisation of mammalian tissues and immune evasion. The molecular complexes that perceive and transmit the fungal pH signal are membrane-proximal and essential for virulence and are therefore of interest as novel antifungal drug targets. Intriguingly, the sensory machinery has evolved divergently in different fungal pathogens, yet spatial co-ordination of cellular components is conserved.

Functional analysis of the kinome reveals a DYRK kinase involved in septal plugging is a novel antifungal drug target.

More than 10 million people suffer from lung diseases caused by the pathogenic fungus . The azole class of antifungals represent first line therapeutics for most of these infections however resistance is rising. Identification of novel antifungal targets that, when inhibited, synergise with the azoles will aid the development of agents that can improve therapeutic outcomes and supress the emergence of resistance.

Heightened Efficacy of Anidulafungin When Used in Combination with Manogepix or 5-Flucytosine against Candida auris .

Candida auris is an emerging, multidrug-resistant fungal pathogen that causes refractory colonization and life-threatening, invasive nosocomial infections. The high proportion of C. auris isolates that display antifungal resistance severely limits treatment options.

Developing novel antifungals: lessons from G protein-coupled receptors.

Up to 1.5 million people die yearly from fungal disease, but the repertoire of antifungal drug classes is minimal and the incidence of drug resistance is rising rapidly. This dilemma was recently declared by the World Health Organization as a global health emergency, but the discovery of new antifungal drug classes remains excruciatingly slow.

Aspergillus fumigatus Drives Tissue Damage via Iterative Assaults upon Mucosal Integrity and Immune Homeostasis.

The human lung is constantly exposed to Aspergillus fumigatus spores, the most prevalent worldwide cause of fungal respiratory disease. Pulmonary tissue damage is a unifying feature of Aspergillus-related diseases; however, the mechanistic basis of damage is not understood. In the lungs of susceptible hosts, A.

Distinct Cohorts of Transcription Factors Are Required for Epithelial Damage Occurring Contact- or Soluble Effector-Mediated Mechanisms.

Damage to the lung epithelium is a unifying feature of disease caused by the saprophytic fungus . However, the mechanistic basis and the regulatory control of such damage is poorly characterized. Previous studies have identified mediated pathogenesis as occurring at early (≤ 16 hours) or late (>16 hours) phases of the fungal interaction with epithelial cells, and respectively involve direct contact with the host cell or the action of soluble factors produced by mature fungal hyphae.

Exploring a novel genomic safe-haven site in the human pathogenic mould Aspergillus fumigatus.

Aspergillus fumigatus is the most important airborne fungal pathogen and allergen of humans causing high morbidity and mortality worldwide. The factors that govern pathogenicity of this organism are multi-factorial and are poorly understood. Molecular tools to dissect the mechanisms of pathogenicity in A.

Tackling the emerging threat of antifungal resistance to human health.

Invasive fungal infections pose an important threat to public health and are an under-recognized component of antimicrobial resistance, an emerging crisis worldwide. Across a period of profound global environmental change and expanding at-risk populations, human-infecting pathogenic fungi are evolving resistance to all licensed systemic antifungal drugs. In this Review, we highlight the main mechanisms of antifungal resistance and explore the similarities and differences between bacterial and fungal resistance to antimicrobial control.

Pathogenesis of Respiratory Viral and Fungal Coinfections.

Individuals suffering from severe viral respiratory tract infections have recently emerged as "at risk" groups for developing invasive fungal infections. Influenza virus is one of the most common causes of acute lower respiratory tract infections worldwide. Fungal infections complicating influenza pneumonia are associated with increased disease severity and mortality, with invasive pulmonary aspergillosis being the most common manifestation.

Fungal and host protein persulfidation are functionally correlated and modulate both virulence and antifungal response.

Aspergillus fumigatus is a human fungal pathogen that can cause devastating pulmonary infections, termed "aspergilloses," in individuals suffering immune imbalances or underlying lung conditions. As rapid adaptation to stress is crucial for the outcome of the host-pathogen interplay, here we investigated the role of the versatile posttranslational modification (PTM) persulfidation for both fungal virulence and antifungal host defense. We show that an A.

Development of a marker-free mutagenesis system using CRISPR-Cas9 in the pathogenic mould Aspergillus fumigatus.

Aspergillus fumigatus is a saprophytic fungal pathogen that is the cause of more than 300,000 life-threatening infections annually. Our understanding of pathogenesis and factors contributing to disease progression are limited. Development of rapid and versatile gene editing methodologies for A.

Targeting Methionine Synthase in a Fungal Pathogen Causes a Metabolic Imbalance That Impacts Cell Energetics, Growth, and Virulence.

There is an urgent need to develop novel antifungals to tackle the threat fungal pathogens pose to human health. Here, we have performed a comprehensive characterization and validation of the promising target methionine synthase (MetH). We show that in the absence of this enzymatic activity triggers a metabolic imbalance that causes a reduction in intracellular ATP, which prevents fungal growth even in the presence of methionine.

Live-cell imaging of rapid calcium dynamics using fluorescent, genetically-encoded GCaMP probes with Aspergillus fumigatus.

Calcium signalling plays a fundamental role in fungal intracellular signalling. Previous approaches (fluorescent dyes, bioluminescent aequorin, genetically encoded cameleon probes) with imaging rapid subcellular changes in cytosolic free calcium ([Ca]) in fungal cells have produced inconsistent results. Recent data obtained with new fluorescent, genetically encoded GCaMP probes, that are very bright, have resolved this problem.

On the lineage of Aspergillus fumigatus isolates in common laboratory use.

Unlabelled: The origin of isolates routinely used by the community of Aspergillus fumigatus researchers is periodically a matter of intense discussion at our centre, as the construction of recombinant isolates have sometimes followed convoluted routes, the documentation describing their lineages is fragmented, and the nomenclature is confusing. As an aide memoir, not least for our own benefit, we submit the following account and tabulated list of strains (Table 1) in an effort to collate all of the relevant information in a single, easily accessible document. To maximise the accuracy of this record we have consulted widely amongst the community of Medical Mycologists using these strains.

The negative cofactor 2 complex is a key regulator of drug resistance in Aspergillus fumigatus.

The frequency of antifungal resistance, particularly to the azole class of ergosterol biosynthetic inhibitors, is a growing global health problem. Survival rates for those infected with resistant isolates are exceptionally low. Beyond modification of the drug target, our understanding of the molecular basis of azole resistance in the fungal pathogen Aspergillus fumigatus is limited.

-Derived Volatile Sulfur Compounds Promote Distal Growth and a Synergistic Pathogen-Pathogen Interaction That Increases Pathogenicity in Co-infection.

Pathogen-pathogen interactions in polymicrobial infections are known to directly impact, often to worsen, disease outcomes. For example, co-infection with and , respectively the most common bacterial and fungal pathogens isolated from cystic fibrosis (CF) airways, leads to a worsened prognosis. Recent studies of microbial cross-talk demonstrated that -derived volatile sulfur compounds (VSCs) can promote growth .

Bayesian Detection of Piecewise Linear Trends in Replicated Time-Series with Application to Growth Data Modelling.

We consider the situation where a temporal process is composed of contiguous segments with differing slopes and replicated noise-corrupted time series measurements are observed. The unknown mean of the data generating process is modelled as a piecewise linear function of time with an unknown number of change-points. We develop a Bayesian approach to infer the joint posterior distribution of the number and position of change-points as well as the unknown mean parameters.

Microbial uptake by the respiratory epithelium: outcomes for host and pathogen.

Intracellular occupancy of the respiratory epithelium is a useful pathogenic strategy facilitating microbial replication and evasion of professional phagocytes or circulating antimicrobial drugs. A less appreciated but growing body of evidence indicates that the airway epithelium also plays a crucial role in host defence against inhaled pathogens, by promoting ingestion and quelling of microorganisms, processes that become subverted to favour pathogen activities and promote respiratory disease. To achieve a deeper understanding of beneficial and deleterious activities of respiratory epithelia during antimicrobial defence, we have comprehensively surveyed all current knowledge on airway epithelial uptake of bacterial and fungal pathogens.

Mechanistic Basis of pH-Dependent 5-Flucytosine Resistance in Aspergillus fumigatus.

The antifungal drug 5-flucytosine (5FC), a derivative of the nucleobase cytosine, is licensed for the treatment of fungal diseases; however, it is rarely used as a monotherapeutic to treat infection. Despite being potent against other fungal pathogens, 5FC has limited activity against when standard assays are used to determine susceptibility. However, in modified assays where the pH is set to pH 5, the activity of 5FC increases significantly.