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Spatial Transcriptomics of Lungs Infected with Coccidioides posadasii

ABSTRACT: Coccidioidomycosis, or Valley Fever, is a lung disease caused by inhaling Coccidioides fungi, prevalent in the Southwestern U.S., Mexico, and parts of Central and South America. Climate change is contributing to the spread of this disease. Many cases are asymptomatic, some are often misdiagnosed, and a small subset can progress to severe illness. To better understand lung responses during late Coccidioides infection, we used 10x Visium spatial transcriptomics. We analyzed non-infected lung (D0) and infected lung at 14 days post-infection (D14).

ORGANISM(S): Mus musculus

PROVIDER: GSE274767 | GEO | 2024/11/13

REPOSITORIES: GEO

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scRNA-seq time-course of Coccidioides posadasii infected lungs

Project description:Coccidioidomycosis, or Valley Fever, is a lung disease caused by inhaling Coccidioides fungi, prevalent in the Southwestern U.S., Mexico, and parts of Central and South America. Climate change is contributing to the spread of this disease. Many cases are asymptomatic, some are often misdiagnosed, and a small subset can progress to severe illness. To better understand lung responses during Coccidioides infection, we used single-cell RNA sequencing (scRNA-seq). We analyzed non-infected lungs (D0) and infected lungs at 5, 9, and 14 days post-infection (D5, D9, D14).

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Project description:The aims of this study were to present modifications to the annotations of the genome of C. posadasii, one of two closely related species of Coccidioides, a dimorphic fungal pathogen that causes coccidioidomycosis, also called Valley Fever. Proteins present in lysates and filtrates of in vitro grown mycelia and parasitic phase spherules from C. posadasii strain Silveira were analyzed using a GeLC-MS/MS method.

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The WOPR family protein Ryp1 is a key regulator of gene expression, development, and virulence in the thermally dimorphic fungal pathogen Coccidioides posadasii

Project description:Coccidioides spp. are fungal pathogens endemic to Southern California, Arizona, and other desert regions where they cause a spectrum of symptoms known as Valley Fever in otherwise healthy individuals. In the soil, Coccidioides grows in a hyphal form that produces vegetative spores (arthroconidia). When arthroconidia are inhaled by mammals they undergo an elaborate developmental transition consisting of germination, multiple rounds of nuclear division, and segmentation to form large spherules filled with vegetative endospores. Very little is understood about the molecular basis of spherule formation. Here we characterize the role of the conserved transcription factor Ryp1 in Coccidioides spherule formation. We show that Coccidioides ryp1 mutants are unable to form mature spherules, instead arresting at an early stage of spherulation. We analyze the transcriptional profile of wild-type and Δryp1 mutant cells under hyphal and spherule-promoting conditions, thereby defining a set of hyphal- or spherule-enriched transcripts that are dependent on Ryp1 for their expression. Ryp1-dependent transcripts include key virulence factors such as SOWgp, which encodes the spherule outer wall glycoprotein. In the mouse model of coccidioidomycosis, we find that the Δryp1 mutant is completely avirulent, indicating that Ryp1-dependent pathways are essential for the ability of Coccidioides to cause disease. Vaccination of C57BL/6 mice with live Δryp1 spores does not provide any protection from lethal C. posadasii intranasal infection, consistent with our findings that the Δryp1 mutant fails to make mature spherules. Taken together, this work identifies the first transcriptional regulator that drives mature spherulation and virulence in Coccidioides.

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AÂ Coccidioides posadasii CPS1Â deletion mutant is avirulent and protects mice from lethal infection

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Coccidioides posadasii

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A Coccidioides posadasii CPS1 deletion mutant is avirulent and protects mice from lethal infection

Project description:The CPS1 gene was identified as a virulence factor in the maize pathogen, Cochliobolus heterostrophus. Hypothesizing that the homologous gene in Coccidioides posadasii (Cp) could be important for virulence, we created a deletion mutant, Δcps1, which was unable to cause disease in three strains of mice (C57BL/6, BALB/c, or the severely immunodeficient NOD-scid,γcnull [NSG]). Only a single colony was recovered from one of 60 C57BL/6 mice following intranasal infections of up to 4400 spores. Following administration of very high doses (10,000 to 2.5 x 10^7 spores) to NSG and BALB/c mice, spherules were observed in lung sections at time points from day 3 to day 10 post-infection, but nearly all appeared degraded with infrequent endosporulation. Although the role of CPS1 in virulence is not understood, phenotypic alterations and transcription differences of at least 33 genes in Δcps1 vs. Cp is consistent with both metabolic and regulatory functions for the gene. The in vitro phenotype of Δcps1 showed slower growth of mycelia with delayed and lower spore production compared to Cp, and in vitro spherules were smaller. Vaccination of C57BL/6 or BALB/c mice with live Δcps1 spores either intranasally, intraperitoneally or subcutaneously resulted in over 95% survival with mean residual lung fungal burdens <1000 colony-forming units from an otherwise lethal Cp intranasal infection. Considering its apparently complete attenuation of virulence and the high degree of resistance to Cp infection when used as a vaccine, Δcps1 is a promising vaccine candidate for preventing coccidioidomycosis in humans or other animals.

2016-08-15 | GSE85364 | GEO

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