Research

18 pages, 1744 KiB

Open AccessArticle

Macrophage and Dendritic Cell Activation and Polarization in Response to Coccidioidesposadasii Infection

by Anh L. Diep, Susana Tejeda-Garibay, Nadia Miranda and Katrina K. Hoyer

J. Fungi 2021, 7(8), 630; https://doi.org/10.3390/jof7080630 - 03 Aug 2021

Cited by 5 | Viewed by 2427

Coccidioidomycosis is a fungal, respiratory disease caused by Coccidioides immitis and Coccidioides posadasii. The host immune responses that define disease outcome during infection are largely unknown, although T helper responses are required. Adaptive immunity is influenced by innate immunity as antigen-presenting cells [...] Read more.

Coccidioidomycosis is a fungal, respiratory disease caused by Coccidioides immitis and Coccidioides posadasii. The host immune responses that define disease outcome during infection are largely unknown, although T helper responses are required. Adaptive immunity is influenced by innate immunity as antigen-presenting cells activate and educate adaptive responses. Macrophage and dendritic cell (DC) recognition of pathogen surface molecules are critical for Coccidioides clearance. We characterize the broad innate immune responses to Coccidioides by analyzing macrophage and dendritic cell responses to Coccidioides arthroconidia using avirulent, vaccine Coccidioides strain NR-166 (Δcts2/Δard1/Δcts3), developed from parental virulent strain C735. We developed a novel flow cytometry-based method to analyze macrophage phagocytosis to complement traditional image-scoring methods. Our study found that macrophage polarization is blocked at M0 phase and activation reduced, while DCs polarize into proinflammatory DC1s, but not anti-inflammatory DC2, following interaction with Coccidioides. However, DCs exhibit a contact-dependent reduced activation to Coccidioides as defined by co-expression of MHC-II and CD86. In vivo, only modest DC1/DC2 recruitment and activation was observed with avirulent Coccidioides infection. In conclusion, the vaccine Coccidioides strain recruited a mixed DC population in vivo, while in vitro data suggest active innate immune cell inhibition by Coccidioides. Full article

(This article belongs to the Special Issue Coccidioides and Coccidioidomycosis 2020)

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15 pages, 1629 KiB

Open AccessArticle

Transcriptional Analysis of Coccidioides immitis Mycelia and Spherules by RNA Sequencing

by Aaron F. Carlin, Sinem Beyhan, Jesús F. Peña, Jason E. Stajich, Suganya Viriyakosol, Joshua Fierer and Theo N. Kirkland

J. Fungi 2021, 7(5), 366; https://doi.org/10.3390/jof7050366 - 07 May 2021

Cited by 10 | Viewed by 2229

Abstract

Coccidioides immitis and C. posadasii are dimorphic fungi that transform from mycelia with internal arthroconidia in the soil to a tissue form known as a spherule in mammals. This process can be recapitulated in vitro by increasing the temperature, CO₂ and [...] Read more.

Coccidioides immitis and C. posadasii are dimorphic fungi that transform from mycelia with internal arthroconidia in the soil to a tissue form known as a spherule in mammals. This process can be recapitulated in vitro by increasing the temperature, CO₂ and changing other culture conditions. In this study, we have analyzed changes in gene expression in mycelia and young and mature spherules. Genes that were highly upregulated in young spherules include a spherule surface protein and iron and copper membrane transporters. Genes that are unique to Coccidioides spp. are also overrepresented in this group, suggesting that they may be important for spherule differentiation. Enriched GO terms in young spherule upregulated genes include oxidation-reduction, response to stress and membrane proteins. Downregulated genes are enriched for transcription factors, especially helix–loop–helix and C2H2 type zinc finger domain-containing proteins, which is consistent with the dramatic change in transcriptional profile. Almost all genes that are upregulated in young spherules remain upregulated in mature spherules, but a small number of genes are differentially expressed in those two stages of spherule development. Mature spherules express more Hsp31 and amylase and less tyrosinase than young spherules. Some expression of transposons was detected and most of the differentially expressed transposons were upregulated in spherules. Full article

(This article belongs to the Special Issue Coccidioides and Coccidioidomycosis 2020)

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14 pages, 1558 KiB

Open AccessArticle

Differential Thermotolerance Adaptation between Species of Coccidioides

by Heather L. Mead, Paris S. Hamm, Isaac N. Shaffer, Marcus de Melo Teixeira, Christopher S. Wendel, Nathan P. Wiederhold, George R. Thompson III, Raquel Muñiz-Salazar, Laura Rosio Castañón-Olivares, Paul Keim, Carmel Plude, Joel Terriquez, John N. Galgiani, Marc J. Orbach and Bridget M. Barker

J. Fungi 2020, 6(4), 366; https://doi.org/10.3390/jof6040366 - 14 Dec 2020

Cited by 15 | Viewed by 3861

Abstract

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 [...] Read more.

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, was screened for mycelial growth rate at 37 °C and 28 °C on solid media. The radial growth rate was measured for 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 °C and 28 °C, respectively. C. posadasii grew significantly faster at 37 °C, when compared to C. immitis; whereas both species had similar growth rates at 28 °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 research. Full article

(This article belongs to the Special Issue Coccidioides and Coccidioidomycosis 2020)

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13 pages, 1874 KiB

Open AccessArticle

Laser Capture Microdissection-Assisted Protein Biomarker Discovery from Coccidioides-Infected Lung Tissue

by Natalie M. Mitchell, Surendra Dasari, Thomas E. Grys and Douglas F. Lake

J. Fungi 2020, 6(4), 365; https://doi.org/10.3390/jof6040365 - 14 Dec 2020

Cited by 1 | Viewed by 2760

Abstract

Laser capture microdissection (LCM) coupled to label-free quantitative mass spectrometry is a viable strategy to identify biomarkers from infected tissues. In this study, LCM was employed to take a “snapshot” of proteins produced in vivo during Coccidiodies spp. infection in human lungs. Proteomic [...] Read more.

Laser capture microdissection (LCM) coupled to label-free quantitative mass spectrometry is a viable strategy to identify biomarkers from infected tissues. In this study, LCM was employed to take a “snapshot” of proteins produced in vivo during Coccidiodies spp. infection in human lungs. Proteomic analysis of LCM lung sections revealed hundreds of hosts and Coccidioidal proteins. Twenty-seven highly abundant Coccidioides spp. proteins were identified which do not share significant sequence orthology with human proteins. Three of the 27 Coccidioidal proteins are also potential Coccidoides-specific biomarkers, as they also do not share sequence homology to any other pathogenic fungus or microbe. Gene ontology analysis of the 27 biomarker candidate proteins revealed enriched hydrolase activity and increased purine and carbohydrate metabolism functions. Finally, we provide proteomic evidence that all 27 biomarker candidates are produced by the fungus when grown in vitro in a media- and growth-phase dependent manner. Full article

(This article belongs to the Special Issue Coccidioides and Coccidioidomycosis 2020)

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14 pages, 7777 KiB

Open AccessArticle

Of Mice and Fungi: Coccidioides spp. Distribution Models

by Pamela Ocampo-Chavira, Ricardo Eaton-Gonzalez and Meritxell Riquelme

J. Fungi 2020, 6(4), 320; https://doi.org/10.3390/jof6040320 - 27 Nov 2020

Cited by 12 | Viewed by 3326

Abstract

The continuous increase of Coccidioidomycosis cases requires reliable detection methods of the causal agent, Coccidioides spp., in its natural environment. This has proven challenging because of our limited knowledge on the distribution of this soil-dwelling fungus. Knowing the pathogen’s geographic distribution and its [...] Read more.

The continuous increase of Coccidioidomycosis cases requires reliable detection methods of the causal agent, Coccidioides spp., in its natural environment. This has proven challenging because of our limited knowledge on the distribution of this soil-dwelling fungus. Knowing the pathogen’s geographic distribution and its relationship with the environment is crucial to identify potential areas of risk and to prevent disease outbreaks. The maximum entropy (Maxent) algorithm, Geographic Information System (GIS) and bioclimatic variables were combined to obtain current and future potential distribution models (DMs) of Coccidioides and its putative rodent reservoirs for Arizona, California and Baja California. We revealed that Coccidioides DMs constructed with presence records from one state are not well suited to predict distribution in another state, supporting the existence of distinct phylogeographic populations of Coccidioides. A great correlation between Coccidioides DMs and United States counties with high Coccidioidomycosis incidence was found. Remarkably, under future scenarios of climate change and high concentration of greenhouse gases, the probability of habitat suitability for Coccidioides increased. Overlap analysis between the DMs of rodents and Coccidioides, identified Neotoma lepida as one of the predominant co-occurring species in all three states. Considering rodents DMs would allow to implement better surveillance programs to monitor disease spread. Full article

(This article belongs to the Special Issue Coccidioides and Coccidioidomycosis 2020)

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12 pages, 240 KiB

Open AccessArticle

Comparative Study of Newer and Established Methods of Diagnosing Coccidioidal Meningitis

by David A. Stevens, Marife Martinez, Gabriele Sass, Demosthenes Pappagianis, Brian Doherty, Hannah Kutsche and Meredith McGuire

J. Fungi 2020, 6(3), 125; https://doi.org/10.3390/jof6030125 - 04 Aug 2020

Cited by 3 | Viewed by 2824

Abstract

Meningitis is the most devastating form of coccidioidomycosis. A convenient, rapid diagnostic method could result in early treatment and avoid many meningitis complications. We studied cerebrospinal fluid (CSF) samples in patients with documented coccidioidal meningitis, and controls, with complement fixation (CF), immunodiffusion (ID) [...] Read more.

Meningitis is the most devastating form of coccidioidomycosis. A convenient, rapid diagnostic method could result in early treatment and avoid many meningitis complications. We studied cerebrospinal fluid (CSF) samples in patients with documented coccidioidal meningitis, and controls, with complement fixation (CF), immunodiffusion (ID) (the “classical” assays), lateral flow assays (LFA; one-strip and two-strip), and two enzyme immunoassays (EIA). The two-strip LFA and EIAs not only enabled separate testing for IgG and IgM antibodies separately, but also could aggregate results for each method. CF with ID or the aggregate use of IgG and IgM tests were considered optimal test uses. LFAs and EIAs were evaluated at 1:21 and 1:441 dilutions of specimens. All assays were compared to true patient status. With 49 patient specimens and 40 controls, this is the largest comparative study of CSF coccidioidal diagnostics. Sensitivity of these tests ranged from 71–95% and specificity 90–100%. IgM assays were less sensitive. Assays at 1:441 were similarly specific but less sensitive, suggesting that serial dilutions of samples could result in assays yielding titers. Agreement of positive results on cases was 87–100%. When kits are available, hospital laboratories in endemic areas can perform testing. LFA assays do not require a laboratory, are simple to use, and give rapid results, potentially even at the bedside. Full article

(This article belongs to the Special Issue Coccidioides and Coccidioidomycosis 2020)

Review

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16 pages, 775 KiB

Open AccessReview

The Known Unknowns of the Immune Response to Coccidioides

by Rebecca A. Ward, George R. Thompson 3rd, Alexandra-Chloé Villani, Bo Li, Michael K. Mansour, Marcel Wuethrich, Jenny M. Tam, Bruce S. Klein and Jatin M. Vyas

J. Fungi 2021, 7(5), 377; https://doi.org/10.3390/jof7050377 - 11 May 2021

Cited by 6 | Viewed by 4828

Abstract

Coccidioidomycosis, otherwise known as Valley Fever, is caused by the dimorphic fungi Coccidioides immitis and C. posadasii. While most clinical cases present with self-limiting pulmonary infection, dissemination of Coccidioides spp. results in prolonged treatment and portends higher mortality rates. While the structure, [...] Read more.

Coccidioidomycosis, otherwise known as Valley Fever, is caused by the dimorphic fungi Coccidioides immitis and C. posadasii. While most clinical cases present with self-limiting pulmonary infection, dissemination of Coccidioides spp. results in prolonged treatment and portends higher mortality rates. While the structure, genome, and niches for Coccidioides have provided some insight into the pathogenesis of disease, the underlying immunological mechanisms of clearance or inability to contain the infection in the lung are poorly understood. This review focuses on the known innate and adaptive immune responses to Coccidioides and highlights three important areas of uncertainty and potential approaches to address them. Closing these gaps in knowledge may enable new preventative and therapeutic strategies to be pursued. Full article

(This article belongs to the Special Issue Coccidioides and Coccidioidomycosis 2020)

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14 pages, 9514 KiB

Open AccessReview

Coccidioidomycosis in Brazil: Historical Challenges of a Neglected Disease

by Rossana Cordeiro, Santiago Moura, Débora Castelo-Branco, Marcos Fábio Rocha, Reginaldo Lima-Neto and José Júlio Sidrim

J. Fungi 2021, 7(2), 85; https://doi.org/10.3390/jof7020085 - 27 Jan 2021

Cited by 3 | Viewed by 2018

Abstract

Coccidioidomycosis is a deep-seated fungal infection that occurs exclusively in semiarid areas in the Americas. In Brazil, coccidioidomycosis occurs exclusively in rural areas in the northeast region and affects counties that are hit by recurrent droughts, poverty and economic stagnation. Since 1978, approximately [...] Read more.

Coccidioidomycosis is a deep-seated fungal infection that occurs exclusively in semiarid areas in the Americas. In Brazil, coccidioidomycosis occurs exclusively in rural areas in the northeast region and affects counties that are hit by recurrent droughts, poverty and economic stagnation. Since 1978, approximately 136 cases of the disease have been reported in Brazil, according to scientific publications. However, a lack of governmental epidemiological data as well as a similarity to tuberculosis have led scientists and experts to assume that a greater number of cases occur in the country, which are not diagnosed and/or reported. In this review, general characteristics of coccidioidomycosis are presented, followed by a description of the main clinical and epidemiological data of cases in Brazil. The purpose of this article is to discuss the inclusion of coccidioidomycosis in the list of neglected tropical diseases. We believe that the adoption of coccidioidomycosis as a neglected tropical disease will enable the creation of an effective epidemiological surveillance system and the development of feasible public health solutions for its control in vulnerable populations. Full article

(This article belongs to the Special Issue Coccidioides and Coccidioidomycosis 2020)

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Other

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12 pages, 573 KiB

Open AccessCase Report

Coccidioidomycosis in Allogeneic Stem Cell Transplant Recipients: Case Series and Review of the Literature

by Christopher F. Saling, Juan Gea-Banacloche, John S. Trickett and Janis E. Blair

J. Fungi 2021, 7(5), 339; https://doi.org/10.3390/jof7050339 - 27 Apr 2021

Cited by 5 | Viewed by 2093

Abstract

Coccidioides is an endemic fungus of the Southwest United States that causes the disease coccidioidomycosis. Immunocompromised persons are at increased risk for severe infection and dissemination. One such population is allogeneic bone marrow transplant (allo-HCT) recipients, but accounts of coccidioidal infection in these [...] Read more.

Coccidioides is an endemic fungus of the Southwest United States that causes the disease coccidioidomycosis. Immunocompromised persons are at increased risk for severe infection and dissemination. One such population is allogeneic bone marrow transplant (allo-HCT) recipients, but accounts of coccidioidal infection in these patients have rarely been documented. We present two cases of Coccidioides in allo-HCT recipients with good outcomes: one patient who developed pulmonary coccidioidomycosis in the late post-engraftment phase and another with known controlled disseminated infection at the time of transplant. A review of the literature identified 19 allo-HCT recipients with coccidioidomycosis. Due to the limited published literature, no guidelines have yet been established regarding optimal prophylaxis and treatment of Coccidioides infection in allo-HCT recipients. Candidates for transplantation should undergo a rigorous pre-transplant assessment to identify evidence of prior or active coccidioidomycosis. In our experience, patients who visit or live in Coccidioides-endemic areas should receive primary prophylaxis for at least the first 100 days post-transplant, and duration should be extended as long as the patient remains on immunosuppression. Those with prior infection should receive secondary prophylaxis while immunosuppressed. Patients with active infection should have treatment and stabilization of infection and continue anti-fungal treatment through immunosuppression. Full article

(This article belongs to the Special Issue Coccidioides and Coccidioidomycosis 2020)

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