De novo GTP Biosynthesis Is Critical for Virulence of the Fungal Pathogen Cryptococcus neoformans

Morrow, Carl A.; Valkov, Eugene; Stamp, Anna; Chow, Eve W. L.; Lee, I. Russel; Wronski, Ania; Williams, Simon J.; Hill, Jennifer; Djordjevic, Julianne T.; Kappler, Ulrike; Kobe, Boštjan; Fraser, James S.

doi:10.1371/journal.ppat.1002957

Cited by 63 publications

(137 citation statements)

References 90 publications

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“…1B). The gua1⌬ strain was not, however, able to utilize the guanine naturally present in rich YPD medium, nor was growth restored by the addition of exogenous guanine to YPD (data not shown); this unusual phenotype was consistent with that previously reported for the IMP dehydrogenase imd1⌬ mutant (25). Reintroducing a wild-type copy of the gene to create strain gua1⌬ϩGUA1 restored growth on both YNB and YPD medium (Fig.…”

Section: Resultssupporting

confidence: 87%

“…3B). Furthermore, fungal burden analysis from sacrificed animals showed the infection had been cleared from all mice infected with the gua1⌬ mutant, similar to previous observations (25).…”

Section: Gmp Synthase Is Critical For C Neoformans Virulence In Bothsupporting

confidence: 89%

“…The pathway is already a target for anticancer drugs (such as mercaptopurine and lometrexol) and immunosuppressants (such as mycophenolic acid) (20 -24). However, the investigation of purine metabolism as an antifungal target has been limited (25)(26)(27).…”

mentioning

confidence: 99%

“…The importance of de novo biosynthesis rather than scavenging while the fungus infects this purine-poor environment was highlighted by the discovery that IMP dehydrogenase, catalyst of the rate-limiting and first committed step in the de novo GTP biosynthesis pathway, is essential for C. neoformans virulence in a murine model. Importantly, structural studies of this enzyme revealed potentially exploitable characteristics of the fungal enzyme not shared with the human isoforms (25).…”

mentioning

confidence: 99%

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GMP Synthase Is Required for Virulence Factor Production and Infection by Cryptococcus neoformans

Chitty

Tatzenko

Williams

et al. 2017

Journal of Biological Chemistry

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Edited by John M. DenuOver the last four decades the HIV pandemic and advances in medical treatments that also cause immunosuppression have produced an ever-growing cohort of individuals susceptible to opportunistic pathogens. Of these, AIDS patients are particularly vulnerable to infection by the encapsulated yeast Cryptococcus neoformans. Most commonly found in the environment in purine-rich bird guano, C. neoformans experiences a drastic change in nutrient availability during host infection, ultimately disseminating to colonize the purine-poor central nervous system. Investigating the consequences of this challenge, we have characterized C. neoformans GMP synthase, the second enzyme in the guanylate branch of de novo purine biosynthesis. We show that in the absence of GMP synthase, C. neoformans becomes a guanine auxotroph, the production of key virulence factors is compromised, and the ability to infect nematodes and mice is abolished. Activity assays performed using recombinant protein unveiled differences in substrate binding between the C. neoformans and human enzymes, with structural insights into these kinetic differences acquired via homology modeling. Collectively, these data highlight the potential of GMP synthase to be exploited in the development of new therapeutic agents for the treatment of disseminated, life-threatening fungal infections.In the past four decades there has been a dramatic escalation in the number of immunocompromised individuals (1). Although many of these are due to advances in immunosuppressive and chemotherapeutic technologies, the largest cohort is a direct result of the AIDS pandemic. Foreshadowed in 1981 with the occurrence of opportunistic Pneumocystis or human herpesvirus 8 infections in previously healthy individuals in Los Angeles (2, 3), AIDS and the lentivirus causing the disease soon gained broad public awareness (4 -6). With the advent of commercial blood testing, national blood bank screening programs were commenced in an effort to slow the spread of this emerging pandemic (7), and in 1987 the first treatment, zidovudine, marked what was thought to be an end to the crisis (8, 9). It was not, as was hoped, a miracle drug; the spread of AIDS continued across the globe and is now believed to have infected over 70 million people and killed 55 million to date (10).Since the discovery of the very first patients identified with Pneumocystis pneumonia, opportunistic fungal pathogens have been tightly linked with the AIDS pandemic. One of the key fungi often encountered in this context is Cryptococcus neoformans, a basidiomycete yeast responsible for cryptococcosis and a major cause of AIDS-related mortality (11). Most commonly found associated with purine-rich bird guano, spores or desiccated yeast cells from this environmental niche are inhaled into the lungs where, in an immunocompromised individual, the fungus can disseminate to the purine-poor central nervous system to cause meningoencephalitis.The fundamental treatment for cryptococcosis has not changed significantly ...

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Section: Resultssupporting

confidence: 87%

Section: Gmp Synthase Is Critical For C Neoformans Virulence In Bothsupporting

confidence: 89%

mentioning

confidence: 99%

mentioning

confidence: 99%

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GMP Synthase Is Required for Virulence Factor Production and Infection by Cryptococcus neoformans

Chitty

Tatzenko

Williams

et al. 2017

Journal of Biological Chemistry

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“…C. elegans was also used to screen virulence factors of C. neoformans (29)(30)(31)(32)(33)(34)(35)(36). Moreover, C. neoformans infection model with C. elegans was also used to evaluate therapeutic effects of antifungal reagents (37,38).…”

Section: Neoformans Infection Models Using Other Invertebrate Modelsmentioning

confidence: 99%

Usefulness of silkworm as a host animal for understanding pathogenicity of <i>Cryptococcus neoformans </i>

Ishii

Matsumoto

Sekimizu

2016

DD&T

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Identification of uric acid as the redox molecule secreted by the yeast Arxula adeninivorans

Williams

Trautwein-Schult

Jankowska

et al. 2014

Appl Microbiol Biotechnol

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The yeast Arxula adeninivorans has been previously shown to secrete a large amount of an electro-active molecule. The molecule was produced by cells that had been cultivated in a rich medium, harvested, washed and then suspended in phosphate-buffered saline (PBS). The molecule was easily detectable after 60 min of incubation in PBS, and the cells continued to produce the molecule in these conditions for up to 3 days. The peak anodic potential of the oxidation peak was 0.42 V, and it was shown to be a solution species rather than a cell-attached species. We have optimised the production of the molecule, identified it by high-pressure liquid chromatography (HPLC) fractionation and high-resolution mass spectrometric analysis and determined the pathway involved in its synthesis. It has a mass/charge ratio that corresponds to uric acid, and this identification was supported by comparing UV spectra and cyclic voltammograms of the samples to those of uric acid. An A. adeninivorans xanthine oxidase gene disruption mutant failed to produce uric acid, which added further validity to this identification. It also demonstrated that the purine catabolism pathway is involved in its production. A transgenic A. adeninivorans strain with a switchable urate oxidase gene (AUOX) accumulated uric acid when the gene was switched off but did not when the gene was switched on. Cultivation of cells on amino acid and purine-free minimal media with an inorganic nitrogen source suggests that the cells synthesise purines from inorganic nitrogen and proceed to degrade them via the normal purine degradation pathway.

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De novo GTP Biosynthesis Is Critical for Virulence of the Fungal Pathogen Cryptococcus neoformans

Cited by 63 publications

References 90 publications

GMP Synthase Is Required for Virulence Factor Production and Infection by Cryptococcus neoformans

GMP Synthase Is Required for Virulence Factor Production and Infection by Cryptococcus neoformans

Usefulness of silkworm as a host animal for understanding pathogenicity of <i>Cryptococcus neoformans </i>

Identification of uric acid as the redox molecule secreted by the yeast Arxula adeninivorans

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