Biology subjects

Thompson, G. R.

Publications and source records attributed to Thompson, G. R..

5 recordsLinked to original sources

bioRxiv2026

Proteome-wide discovery of novel diagnostic antigens for coccidioidomycosis

Coccidioidomycosis, commonly called Valley Fever (VF), caused by Coccidioides spp., is an understudied fungal disease that accounts for a substantial fraction of pneumonias in endemic areas. Diagnosis remains challenging because the mainstay of diagnosis is serology, and current assays have modest sensitivity in early infection. Discovery of new antigens could improve serologic detection early in disease. Here, we use PepSeq, a DNA-programmable serology platform, to represent the complete proteome of Coccidioides within a library of 244,000 DNA-barcoded peptides. By profiling antibody reactivity at the protein and epitope levels in VF patients, naturally infected pigtail macaques, and healthy controls, we identify numerous previously-unrecognized antigens and epitopes, including some shared between humans and macaque responses. When translated into a pooled peptide ELISA, we show that a subset of identified antigens can discriminate VF cases from controls in an independent cohort with high accuracy (AUC = 0.91). These findings establish high-dimensional peptide serology as a scalable approach for fungal antigen discovery and identify new targets for improved VF diagnosis.

immunology↗

bioRxiv2024

Single-cell analysis of human airway epithelium identifies cell type-specific responses to Aspergillus and Coccidioides

Respiratory fungal infections pose a significant threat to human health. Animal models do not fully recapitulate human disease, necessitating advanced models to study human-fungal pathogen interactions. In this study, we utilized primary human airway epithelial cells (hAECs) to recapitulate the lung environment in vitro and investigate cellular responses to two diverse, clinically significant fungal pathogens, Aspergillus fumigatus and Coccidioides posadasii. To understand the mechanisms of early pathogenesis for both fungi, we performed single-cell RNA sequencing of infected hAECs. Analysis revealed that both fungi induced cellular stress and cytokine production. However, the cell subtypes affected and specific pathways differed between fungi, with A. fumigatus and C. posadasii triggering protein-folding-related stress in ciliated cells and hypoxia responses in secretory cells, respectively. This study represents one of the first reports of single-cell transcriptional analysis of hAECs infected with either A. fumigatus or C. posadasii, providing a vital dataset to dissect the mechanism of disease and potentially identify targetable pathways. ImportanceFungal infections in the lungs are dreaded complications for those with compromised immune systems and have limited treatment strategies available. These options are restricted further by the increased prevalence of treatment-resistant fungi. Many studies focus on how our immune systems respond to these pathogens, yet airway epithelial cells remain an understudied component of fungal infections in the lungs. Here, the authors provide a transcriptional analysis of primary human airway epithelial cells stimulated by two distinct fungal pathogens, Aspergillus fumigatus and Coccidioides posadasii. These data will enable further mechanistic studies of the contribution of the airway epithelium to initial host responses and represent a powerful new resource for investigators.

immunology↗

bioRxiv2024

Discovery and Repurposing of Pharmaceutical Agents as Antifungals: In vivo activity against Coccidioides

There is significant interest in identifying improved treatments for coccidioidomycosis, an endemic fungal infection found in the southwestern United States, and Central and South America. The current standard of care, fluconazole, often fails to completely eradicate Coccidioides infection; however, the cost of identifying new compounds is often high in terms of both finances and time. Therefore, repurposing existing pharmaceutical agents is an attractive option. In our previous work, we identified several compounds which inhibited fungal growth in vitro. Based on these findings, we screened a subset of these agents to increase the performance of fluconazole in a combination therapy approach, as compared to fluconazole alone, in a murine model. We observed that combination therapy of sertraline:fluconazole significantly reduced the amount of live fungus in the lung compared to fluconazole alone. These results suggest that sertraline can be repurposed as an adjunctive agent in the treatment of this important fungal disease.

microbiology↗

bioRxiv2021

A chromosomal-level reference genome of the widely utilized Coccidioides posadasii laboratory strain "Silveira"

Coccidioidomycosis is a common fungal disease that is endemic to arid and semi-arid regions of both American continents. Coccidioides immitis and C. posadasii are the etiological agents of the disease, also known as Valley Fever. For several decades, the C. posadasii strain Silveira has been used widely in vaccine studies, is the source strain for production of diagnostic antigens, and is a widely used experimental strain for functional studies. In 2009, the genome was sequenced using Sanger sequencing technology, and a draft assembly and annotation was made available. In the current study, the genome of the Silveira strain was sequenced using Single Molecule Real Time Sequencing (SMRT) PacBio technology, assembled into chromosomal-level contigs, genotyped, and the genome was reannotated using sophisticated and curated in silico tools. This high-quality genome sequencing effort has improved our understanding of chromosomal structure, gene set annotation, and lays the groundwork for identification of structural variants (e.g. transversions, translocations, and copy number variants), assessment of gene gain and loss, and comparison of transposable elements in future phylogenetic and population genomics studies.

genomics↗

bioRxiv2020

Differential thermotolerance adaptation between species of Coccidioides

Coccidioidomycosis, or Valley fever, is caused by two species of dimorphic fungi. Based on molecular phylogenetic evidence, the genus Coccidioides contains two reciprocally monophyletic species: C. immitis and C. posadasii. However, phenotypic variation between species has not been deeply investigated. We therefore explored differences in growth rate under various conditions. A collection of 39 C. posadasii and 46 C. immitis isolates, representing the full geographical range of the two species, were screened for mycelial growth rate at 37{degrees}C and 28{degrees}C on solid media. The radial growth rate was measured over 16 days on yeast extract agar. A linear mixed effect model was used to compare the growth rate of C. posadasii and C. immitis at 37{degrees}C and 28{degrees}C respectively. C. posadasii grew significantly faster at 37{degrees}C, when compared to C. immitis; whereas both species had similar growth rates at 28{degrees}C. These results indicate thermotolerance differs between these two species. As the ecological niche has not been well-described for Coccidioides spp., and disease variability between species has not been shown, the evolutionary pressure underlying the adaptation is unclear. However, this research reveals the first significant phenotypic difference between the two species that directly applies to ecological and clinical research.

microbiology↗