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The role of the NADPH oxidase complex in the defense against Aspergillus nidulans clinical isolates

ABSTRACT: Epidemiological data indicate that Aspergillus nidulans shows a unique association with patients with chronic granulomatous disease (CGD), accounting for the prevalence of fungal infections in this population. The mechanisms underlying this association remain poorly understood. We characterized 24 clinical A. nidulans isolates through genomic sequencing, phenotypic profiling, and host-pathogen interaction studies using wild-type and gp91phox⁻/⁻ (CGD) murine macrophages, complemented by in vivo apocynin-treated murine models. Pangenome analysis revealed a predominantly closed genome (82.2% core) with geographic population structure and strain-specific biosynthetic gene clusters. Phenotypic characterization showed substantial strain-to-strain variability in stress responses, antifungal susceptibility, and cell wall architecture. While CGD macrophages exhibited reduced ROS and increased conidial survival, only a subset of A. nidulans isolates demonstrated virulence comparable to A. fumigatus. Transcriptional profiling identified strain-specific immune modulation, with one isolate exhibiting distinct immune-evasion signatures. Apocynin treatment paradoxically protected against A. fumigatus (70% to 40% lethality) but not A. nidulans, reflecting differential inflammatory responses. Our findings challenge the notion that A. nidulans possesses unique virulence attributes predisposing it to CGD. The epidemiological association likely reflects strain-specific determinants, species misidentification within the A. nidulans complex, and host immune context. Virulence appears to be a distributed property rather than a species-level trait, emphasizing the need for individualized isolate characterization.

ORGANISM(S): Mus musculus

PROVIDER: GSE342884 | GEO | 2026/08/13

REPOSITORIES: GEO

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Project description:Among the most central questions in Leishmania research is why some species remain in the skin dermis at the site of infection by the sand fly vector whereas other species migrate to visceral organs where they cause fatal visceral leishmaniasis. Although L. donovani is the species typically responsible for visceral leishmaniasis, an atypical L. donovani strain is the etiologic agent for cutaneous leishmaniasis in Sri Lanka. To identify molecular determinants for visceral disease, we have analysed the phenotype and genotype of two L. donovani clinical isolates from Sri Lanka where one isolate was derived from a cutaneous leishmaniasis patient (CL) and the other from a visceral leishmaniasis patient (VL). These isolates cause dramatically different pathology when introduced into mice; notably the CL isolate has lost the ability to survive in visceral organs while the VL isolate was highly virulent in visceral organs of BALB/c mice. Whole genome sequencing of the CL and VL isolates revealed that these genomes were very similar as there were no gene deletions and few individual gene amplifications. Indels resulting in frame shifts and loss/gain of stop codons resulted in 13 distinct pseudogenes present in each of the CL and VL isolates. There were 154 non-synonymous SNPs specific to the CL isolate and 193 non-synonymous SNPs specific to the VL isolate. Genome wide gene expression analysis revealed several transcript level differences, including the A2 virulence gene resulting in higher expression of A2 proteins in the VL isolate than in the CL isolate. Genotypic variations relevant to pathology and tropism in Leishmania can be interrogated by reverse genetics. Experimentally increasing A2 expression in the CL isolate through gene transfer significantly increased it’s ability to survive in the spleen of BALB/c mice and conversely, down-regulating A2 expression in the VL isolate abrogated attenuated its survival in BALB/c mice. These observations reveal that there are relatively few genetic differences between the CL and VL isolates apart from the A2 genes, but collectively these have profound effects on human disease and experimentally infected mice.

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The role of the NADPH oxidase complex in the defense against Aspergillus nidulans clinical isolates

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