Elevated mutation rates in multi-azole resistant Aspergillus fumigatus drive rapid evolution of antifungal resistance.

The environmental use of azole fungicides has led to selective sweeps across multiple loci in the Aspergillus fumigatus genome causing the rapid global expansion of a genetically distinct cluster of resistant genotypes. Isolates within this cluster are also more likely to be resistant to agricultural antifungals with unrelated modes of action. Here we show that this cluster is not only multi-azole resistant but has increased propensity to develop resistance to next generation antifungals because of variants in the DNA mismatch repair system.

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.

Fungal diseases in Africa: Closing the gaps in diagnosis and treatment through implementation research and advocacy.

Fungal diseases impose an escalating burden on public health in Africa, exacerbated by issues such as delayed diagnosis, inadequate therapy, and limited access to healthcare resources, resulting in significant morbidity and mortality. Effectively tackling these challenges demands a comprehensive approach encompassing research, training, and advocacy initiatives. Recent clinical mycology surveys conducted by Global Action for Fungal Infection (GAFFI) and the European Confederation of Medical Mycology/International Society for Human and Animal Mycology (ECMM/ISHAM) have underscored gaps in fungal diagnostics and the availability and accessibility of antifungal therapy in Africa.

Re-estimation of the burden of serious fungal diseases in Uganda.

Background: It is of utmost importance to monitor any change in the epidemiology of fungal diseases that may arise from a change in the number of the at-risk population or the availability of local data.

Objective: We sought to update the 2015 publication on the incidence and prevalence of serious fungal diseases in Uganda.

Methods: Using the Leading International Fungal Education methodology, we reviewed published data on fungal diseases and drivers of fungal diseases in Uganda.

Aspergillus fumigatus mitogen-activated protein kinase MpkA is involved in gliotoxin production and self-protection.

Aspergillus fumigatus is a saprophytic fungus that can cause a variety of human diseases known as aspergillosis. Mycotoxin gliotoxin (GT) production is important for its virulence and must be tightly regulated to avoid excess production and toxicity to the fungus. GT self-protection by GliT oxidoreductase and GtmA methyltransferase activities is related to the subcellular localization of these enzymes and how GT can be sequestered from the cytoplasm to avoid increased cell damage.

Aspergillus fumigatus strains that evolve resistance to the agrochemical fungicide ipflufenoquin in vitro are also resistant to olorofim.

Widespread use of azole antifungals in agriculture has been linked to resistance in the pathogenic fungus Aspergillus fumigatus. We show that exposure of A. fumigatus to the agrochemical fungicide, ipflufenoquin, in vitro can select for strains that are resistant to olorofim, a first-in-class clinical antifungal with the same mechanism of action.

Frequency of fungal pathogens in autopsy studies of people who died with HIV in Africa: a scoping review.

Background: Fungal infections are common in HIV-infected individuals and significantly contribute to mortality. However, a substantial number of cases are undiagnosed before death.

Objective: To determine the frequency of fungal pathogens in autopsy studies of people who died with HIV in Africa.

Prevalence of chronic pulmonary aspergillosis along the continuum of pulmonary tuberculosis care: A protocol for a living systematic review and meta-analysis.

Introduction: Chronic pulmonary aspergillosis (CPA) is a debilitating disease estimated to affect over 3 million people worldwide. Pulmonary tuberculosis (PTB) is the most significant risk factor for CPA. However, the true burden of CPA at the time of PTB diagnosis, during, and after PTB treatment remains unknown.

A phylogenetic approach to explore the conidial surface-associated proteome and its role in pathogenesis.

, an important pulmonary fungal pathogen causing several diseases collectively called aspergillosis, relies on asexual spores (conidia) for initiating host infection. Here, we used a phylogenomic approach to compare proteins in the conidial surface of , two closely related non-pathogenic species, and , and the cryptic pathogen . After identifying 62 proteins uniquely expressed on the conidial surface, we assessed null mutants for 42 genes encoding conidial proteins.

A phylogenetic approach to explore the conidial surface-associated proteome and its role in pathogenesis.

, an important pulmonary fungal pathogen causing several diseases collectively called aspergillosis, relies on asexual spores or conidia for initiating host infection. Here, we used a phylogenomic approach to compare proteins in the conidial surface of , two closely related non-pathogenic species, and , and the cryptic pathogen . After identifying 62 proteins uniquely expressed on the conidial surface, we deleted 42 genes encoding conidial proteins.

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.

Vacuoles and peroxisomes are involved in gliotoxin production and self-protection.

is a saprophytic fungus that can cause a variety of human diseases known as aspergillosis. Mycotoxin gliotoxin (GT) production is important for its virulence and must be tightly regulated to avoid excess production and toxicity to the fungus. GT self-protection by GliT oxidoreductase and GtmA methyltransferase activities is related to the subcellular localization of these enzymes and how GT can be sequestered from the cytoplasm to avoid increased cell damage.

The CH transcription factor SltA is required for germination and hyphal development in .

Germination of inhaled conidia is a necessary sequitur for infection. Germination of conidia starts with the breaking of dormancy, which is initiated by an increase of the cellular perimeter in a process termed isotropic growth. This swelling phase is followed by polarized growth, resulting in the formation of a germ tube.

COVID-19-Associated Pulmonary Aspergillosis Isolates Are Genomically Diverse but Similar to Each Other in Their Responses to Infection-Relevant Stresses.

Secondary infections caused by the pulmonary fungal pathogen Aspergillus fumigatus are a significant cause of mortality in patients with severe coronavirus disease 19 (COVID-19). Even though epithelial cell damage and aberrant cytokine responses have been linked to susceptibility to COVID-19-associated pulmonary aspergillosis (CAPA), little is known about the mechanisms underpinning copathogenicity. Here, we analyzed the genomes of 11 A.

Antagonism of the Azoles to Olorofim and Cross-Resistance Are Governed by Linked Transcriptional Networks in Aspergillus fumigatus.

Aspergillosis, in its various manifestations, is a major cause of morbidity and mortality. Very few classes of antifungal drugs have been approved for clinical use to treat these diseases and resistance to the first-line therapeutic class, the triazoles are increasing. A new class of antifungals that target pyrimidine biosynthesis, the orotomides, are currently in development with the first compound in this class, olorofim in late-stage clinical trials.

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.