@entity364 are often difficult to treat due to the inherent similarities between fungal and animal cells and the resulting host @entity137 from many antifungal compounds. @entity1327 is an opportunistic fungal pathogen of @entity1 that causes life-threatening disease, primarily in immunocompromised patients. Since antifungal therapy for this microorganism is limited, many investigators have explored novel drug targets aim at virulence factors, such as the ability to grow at @entity1 physiological temperature (37  C). To address this issue, we used the @entity3261 gene delivery system to create a random insertion mutagenesis library that was screened for altered growth at elevated temperatures. Among several mutants unable to grow at 37  C, we explored one bearing an interruption in the URA4 gene. This gene encodes dihydroorotase (DHOase) that is involved in the de novo synthesis of @entity30114 . Loss of the @entity1327 Ura4 protein, by targeted gene interruption, resulted in an expected @entity5537 / @entity6683 auxotrophy and an unexpected high temperature growth defect. In addition, the ura4 mutant displayed @entity66 in other prominent virulence factors (melanin, capsule and phospholipase) and reduced stress response compared to wild type and reconstituted strains. Accordingly, this mutant had a decreased survival rate in macrophages and attenuated virulence in a @entity19 model of @entity281 . Quantitative PCR analysis suggests that this biosynthetic pathway is induced during the transition from 30  C to 37  C, and that transcriptional regulation of de novo and salvage @entity7391 pathway are under the control of the Ura4 protein.

The role of the de novo @entity7391 biosynthetic pathway in XXXX high temperature growth and virulence.

@entity1 :: ('9606', 'Species') :: ['mammalian', 'humans'] @entity137 :: ('MESH:D064420', 'Disease') :: ['toxicity'] @entity3261 :: ('358', 'Species') :: ['Agrobacterium tumefaciens'] @entity66 :: ('MESH:D004194', 'Disease') :: ['phenotypic defects'] @entity19 :: ('10090', 'Species') :: ['murine'] @entity1327 :: ('5207', 'Species') :: ['Cryptococcus neoformans', 'C. neoformans'] @entity281 :: ('MESH:D007239', 'Disease') :: ['cryptococcal infection'] @entity364 :: ('MESH:D009181', 'Disease') :: ['Fungal infections'] @entity5537 :: ('MESH:D014498', 'Chemical') :: ['uracil'] @entity30114 :: ('CHEBI:26446', 'Chemical') :: ['pyrimidine ribonucleotides'] @entity7391 :: ('MESH:C030986', 'Chemical') :: ['pyrimidine'] @entity6683 :: ('MESH:D014529', 'Chemical') :: ['uridine']
@entity1327 :: (5207,Species) :: ['Cryptococcus neoformans']
