Virulence Mechanisms of<i>Coccidioides</i>

Cole, Garry T.; Xue, Jianmin; Seshan, K. R.; Borra, Priscila; Borra, Ricardo Carneiro; Tarcha, Eric J.; Schaller, Ruth A.; Yu, Jieh Juen; Hung, Chiung Yu

doi:10.1128/9781555815776.ch26

Cited by 14 publications

(8 citation statements)

References 187 publications

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“…Two species have been characterised based on molecular and biogeographical differences: Coccidioides immitis , which appears to be restricted to San Joaquin Valley of California, and C. posadasii , which is widespread throughout regions of endemicity in south‐western USA and northern Mexico (Fisher et al ., ). The multicellular hyphal form of this ascomycete can septate into single‐celled arthroconidia and be inhaled, to cause potentially life‐threatening pneumonia in both immunocompromised and immunocompetent individuals (Cole et al ., ).…”

Section: Fungal Pathogens Of Humansmentioning

confidence: 97%

Nitrogen regulation of virulence in clinically prevalent fungal pathogens

Lee

Morrow

Fraser

2013

FEMS Microbiol Lett

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The habitats of fungal pathogens range from environmental to commensal, and the nutrient content of these different niches varies considerably. Upon infection of humans, nutrient availability changes significantly depending on the site and pathophysiology of infection. Nonetheless, a common feature enabling successful establishment in these niches is the ability to metabolise available nutrients including sources of nitrogen, carbon and essential metals such as iron. In particular, nitrogen source utilisation influences specific morphological transitions, sexual and asexual sporulation and virulence factor production. All these physiological changes confer selective advantages to facilitate fungal survival, proliferation and colonisation. The three most well-studied components of the nitrogen regulatory circuit that commonly impact fungal pathogenesis are the ammonium permeases (the nitrogen availability sensor candidate), ureases (a nitrogen-scavenging enzyme) and GATA transcription factors (global regulators of nitrogen catabolism). In certain species, the ammonium permease induces a morphological switch from yeast to invasive filamentous growth forms or infectious spores, while in others, urease is a bona fide virulence factor. In all species studied thus far, transcription of the ammonium permease and urease-encoding genes is modulated by GATA factors. Fungal pathogens therefore integrate the expression of different virulence-associated phenotypes into the regulatory network controlling nitrogen catabolism.

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Section: Fungal Pathogens Of Humansmentioning

confidence: 97%

Nitrogen regulation of virulence in clinically prevalent fungal pathogens

Lee

Morrow

Fraser

2013

FEMS Microbiol Lett

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“…are diphasic fungi characterized by a parasitic cycle that is unique among the medically important fungi (15). The saprobic phase of Coccidioides grows as a filamentous (hyphal) form and produces small, dry spores (arthroconidia) that are released into the air upon disturbance of the soil.…”

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confidence: 99%

Interleukin-1 Receptor but Not Toll-Like Receptor 2 Is Essential for MyD88-Dependent Th17 Immunity to Coccidioides Infection

et al. 2014

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Interleukin-17A (IL-17A)-producing CD4؉ T helper (Th17) cells have been shown to be essential for defense against pulmonary infection with Coccidioides species. However, we have just begun to identify the required pattern recognition receptors and understand the signal pathways that lead to Th17 cell activation after fungal infection. We previously reported that Card9 ؊/؊ mice vaccinated with formalin-killed spherules failed to acquire resistance to Coccidioides infection. Here, we report that both MyD88 ؊/؊ and Card9 ؊/؊ mice immunized with a live, attenuated vaccine also fail to acquire protective immunity to this respiratory disease. Like Card9 ؊/؊ mice, vaccinated MyD88 ؊/؊ mice revealed a significant reduction in numbers of both Th17 and Th1 cells in their lungs after Coccidioides infection. Both Toll-like receptor 2 (TLR2) and IL-1 receptor type 1 (IL-1r1) upstream of MyD88 have been implicated in Th17 cell differentiation. Surprisingly, vaccinated TLR2 ؊/؊ and wild-type (WT) mice showed similar outcomes after pulmonary infection with Coccidioides, while vaccinated IL-1r1 ؊/؊ mice revealed a significant reduction in the number of Th17 cells in their infected lungs compared to WT mice. Thus, activation of both IL-1r1/MyD88-and Card9-mediated Th17 immunity is essential for protection against Coccidioides infection. Our data also reveal that the numbers of Th17 cells were reduced in IL-1r1 ؊/؊ mice to a lesser extent than in MyD88 ؊/؊ mice, raising the possibility that other TLRs are involved in MyD88-dependent Th17 immunity to coccidioidomycosis. An antimicrobial action of Th17 cells is to promote early recruitment of neutrophils to infection sites. Our data revealed that neutrophils are required for vaccine immunity to this respiratory disease.

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“…Although Coccidioides is recognized as the causative agent of an intransigent infectious disease by physicians who treat patients with the life-threatening, disseminated form of coccidioidomycosis, few virulence factors have been identified for this pathogen [9]. A candidate factor is the propensity of Coccidioides to generate high concentrations of extracellular ammonia at sites of lung infection resulting in an alkaline microenviroment during growth of its parasitic phase in vivo, a condition which has been suggested to compromise host cellular immune defenses [10].…”

Section: Introductionmentioning

confidence: 99%

Extracellular ammonia at sites of pulmonary infection with Coccidioides posadasii contributes to severity of the respiratory disease

Wise

Hung

Whiston

et al. 2013

Microbial Pathogenesis

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Coccidioides is the causative agent of a potentially life-threatening respiratory disease of humans. A feature of this mycosis is that pH measurements of the microenvironment of pulmonary abscesses are consistently alkaline due to ammonia production during the parasitic cycle. We previously showed that enzymatically active urease is partly responsible for elevated concentrations of extracellular ammonia at sites of lung infection and contributes to both localized host tissue damage and exacerbation of the respiratory disease in BALB/c mice. Disruption of the urease gene (URE) of C. posadasii only partially reduced the amount of ammonia detected during in vitro growth of the parasitic phase, suggesting that other ammonia-producing pathways exist that may also contribute to the virulence of this pathogen. Ureidoglycolate hydrolase (Ugh) expressed by bacteria, fungi and higher plants catalyzes the hydrolysis of ureidoglycolate to yield glyoxylate and the release CO2 and ammonia. This enzymatic pathway is absent in mice or humans. Ureidoglycolate hydrolase gene deletions were conducted in a wild type (WT) isolate of C. posadasii as well as the previously generated Δure knock-out strain. Restorations of UGH in the mutant stains were performed to generate and evaluate the respective revertants. The double mutant revealed a marked decrease in the amount of extracellular ammonia without loss of reproductive competence in vitro compared to both the WT and Δure parental strains. BALB/c mice challenged intranasally with the Δugh/Δure mutant showed 90% survival after 30 days, decreased fungal burden, and well-organized pulmonary granulomas. We conclude that loss of both Ugh and Ure activity significantly reduced the virulence of this fungal pathogen.

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Virulence Mechanisms ofCoccidioides

Cited by 14 publications

References 187 publications

Nitrogen regulation of virulence in clinically prevalent fungal pathogens

Nitrogen regulation of virulence in clinically prevalent fungal pathogens

Interleukin-1 Receptor but Not Toll-Like Receptor 2 Is Essential for MyD88-Dependent Th17 Immunity to Coccidioides Infection

Extracellular ammonia at sites of pulmonary infection with Coccidioides posadasii contributes to severity of the respiratory disease

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