The role of reactive oxygen intermediates in experimental coccidioidomycois in mice

<p>Abstract</p> <p>Background</p> <p>Coccidioidomycosis is usually a self-limited infection in immunocompentent people. In immunocompentent human beings second infections due to <it>Coccidioides </it>are very rare, indicating that recovery from infection results in protective immunity. In experimental animals, immunization with several different proteins or attenuated mutants protects against a virulent challenge. To explore what mechanisms are responsible for protective immunity, we investigated the course of <it>Coccidioides </it>infection in the gp91^phoxknock out mouse that has a defect in the oxidative burst that results in chronic granulomatous disease.</p> <p>Results</p> <p>We found that the gp91^phoxknock out mice were somewhat more resistant to intraperitoneal infection and equally as resistant to low dose intranasal infection, but slightly more susceptible to high dose intranasal infection compared to control mice. The gp91^phoxknock out mice made a more robust inflammatory response to infection than controls, as measured by histology and production of inflammatory cytokines. The gp91^phoxknock out mice were as protected by immunization with the recombinant <it>Coccidioides </it>protein Ag2/PRA as the controls were against either intraperitoneal or intranasal infection. <it>Coccidioides immitis </it>arthroconidia and spherules were significantly more resistant to H₂O₂treatment in vitro than <it>Aspergillus fumigatus </it>spores.</p> <p>Conclusion</p> <p>These data suggest that oxidative burst may not be required for protective immunity to coccidioidomycois.</p

Coccidioides Species: A Review of Basic Research: 2022.

Coccidioides immitis and posadasii are closely related fungal species that cause coccidioidomycosis. These dimorphic organisms cause disease in immunocompetent as well as immunocompromised individuals and as much as 40% of the population is infected in the endemic area. Although most infections resolve spontaneously, the infection can be prolonged and, in some instances, fatal. Coccidioides has been studied for more than 100 years and many aspects of the organism and the disease it causes have been investigated. There are over 500 manuscripts concerning Coccidioides (excluding clinical articles) referenced in PubMed over the past 50 years, so there is a large body of evidence to review. We reviewed the most accurate and informative basic research studies of these fungi including some seminal older studies as well as an extensive review of current research. This is an attempt to gather the most important basic research studies about this fungus into one publication. To focus this review, we will discuss the mycology of the organism exclusively rather than the studies of the host response or clinical studies. We hope that this review will be a useful resource to those interested in Coccidioides and coccidioidomycosis

The Quest for a Vaccine Against Coccidioidomycosis: A Neglected Disease of the Americas

Coccidioidomycosis (Valley Fever) is a disease caused by inhalation of Coccidioides spp. This neglected disease has substantial public health impact despite its geographic restriction to desert areas of the southwestern U.S., Mexico, Central and South America. The incidence of this infection in California and Arizona has been increasing over the past fifteen years. Several large cities are within the endemic region in the U.S. Coccidioidomycosis accounts for 25,000 hospital admissions per year in California. While most cases of coccidioidomycosis resolve spontaneously, up to 40% are severe enough to require anti-fungal treatment, and a significant number disseminate beyond the lungs. Disseminated infection involving the meninges is fatal without appropriate treatment. Infection with Coccidioides spp. is protective against a second infection, so vaccination seems biologically plausible. This review of efforts to develop a vaccine against coccidioidomycosis focuses on vaccine approaches and the difficulties in identifying protein antigen/adjuvant combinations that protect in experimental mouse models. Although the quest for a vaccine is still in the early stage, scientific efforts for vaccine development may pave the way for future success

Special Issue: Genomic Data in Pathogenic Fungi.

This special issue, "Genomic Data in Pathogenic Fungi," focuses on the genomics of human and plant pathogens. Efforts like this are important because so little information about these organisms is available.[...]

Genetic differences between Coccidioides spp. and closely related nonpathogenic Onygenales

AbstractCoccidioides spp. are dimorphic, pathogenic fungi that can cause severe human and animal disease. Like the other primary fungal pathogens, animal infection results in a morphologic transformation from the environmental mycelial phase to a tissue phase, known as a spherule. The sequencing and annotation of Coccidioides spp. and the genomes of several nonpathogenic Onygenales species allows comparisons that provide clues about the Coccidioides spp. genes that might be involved in pathogenesis. The analysis in this study is a gene by gene orthology comparison. Although there were few differences in the size of genes families in the Coccidioides spp.-specific group compared to the genes shared by Coccidioides spp. and nonpathogenic Onygenales, there were a number of differences in the characterization of the two types of genes. Many more Coccidioides spp.-specific genes are up-regulated expression in spherules. Coccidioides spp.-specific genes more often lacked functional annotation and were more often classified as orphan genes. Analysis by random forest machine learning confirmed that high numbers of orthologs and high levels of expression in hyphae were predictive of common genes, while high levels of expression in spherules and more nonsynonymous predicted Coccidioides spp.-specific genes. Review of individual genes in the Coccidioides spp.-specific group identified a histidine kinase, two thioredoxin genes, a calmodulin gene and ureidoglycolate hydrolase. Hopefully, identification of these genes will be useful for pursuing potential Coccidioides spp. virulence genes in the future

A few shared up-regulated genes may influence conidia to yeast transformation in dimorphic fungal pathogens.

The small number of fungi that commonly cause disease in normal people share the capacity to grow as mycelia in the soil at 25°C and as yeast (or spherules) in mammals at 37°C. This remarkable conversion has long been a topic of interest in medical mycology. The conidia to yeast conversion has been studied by transcription profiling in several fungal species, including Histoplasma capsulatum, Paracoccidioides brasiliensis, Coccidioides spp., Blastomyces dermatitidis, and Talaromyces marneffei One limitation of transcriptional profiling is determining which genes are involved in the process of conversion to yeast as opposed to a result of conversion to yeast. If there are genes that are up-regulated in the yeast phase of more than one dimorphic, pathogenic fungus they might be required for conversion to yeast (or spherules). To address this issue, 24 up-regulated genes common to Coccidioides spp spherules and H. capsulatum yeasts were identified. Four homologs of these genes were also found in P. brasiliensis, B. dermatitidis or T. marneffei genes that were up-regulated in yeast. 4-hydroxyphenylpurvate dioxygenase, a gene involved in tyrosine metabolism and melanin synthesis that has been shown to be required for yeast conversion, is conserved and up-regulated in yeast in all five species. Another up-regulated gene that is conserved in all five species is a MFS sugar porter. These results suggest that a minority of up-regulated yeast (or spherule) genes are conserved across species and raises the possibility that conserved up-regulated genes may be of special interest for differentiation of mycelium into yeast

Innate Immune Receptors and Defense Against Primary Pathogenic Fungi.

The innate immune system is critical for natural resistance to all pathogenic microorganisms, including fungi. The innate response plays a vital role in resistance to infections before the antigen-specific immune response and also influences antigen-specific adaptive immunity. There are many different receptors for the innate immune response to fungi, and some receptors have been found to play a significant role in the response to human infections with opportunistic fungi. Most human infections are caused by opportunistic fungi, but a small number of organisms are capable of causing infections in normal hosts. The primary pathogenic fungi that cause invasive infections include Blastomyces spp., Cryptococcus gattii, Coccidioides spp., Histoplasma spp., and Paracoccidioides spp. In this review of innate immune receptors that play a role in infections caused by these organisms, we find that innate immunity differs between organisms