Urease of Aspergillus fumigatus Is Required for Survival in Macrophages and Virulence

Xiong, Zhuo; Zhang, Nan; Xu, Liru; Deng, Zhiduo; Limwachiranon, Jarukitt; Guo, Yaojie; Han, Yi; Yang, Wei; Scharf, Daniel H.

doi:10.1128/spectrum.03508-22

Cited by 7 publications

(4 citation statements)

References 80 publications

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“…Urease is critical for the growth of A. fumigatus, urea being the sole nitrogen source of this fungus. In studies carried out by Xiong et al [92], there was an increase in the transcriptional level of urease mRNA after A. fumigatus was grown in urea media. It was demonstrated that a urease mutation in S. cerevisiae led to an increased expression of NCR-regulated genes under conditions of repression [93][94][95].…”

Section: Discussionmentioning

confidence: 96%

Proteomics of Paracoccidioides lutzii: Overview of Changes Triggered by Nitrogen Catabolite Repression

Cruz-Leite,

Moreira,

Silva

et al. 2023

JoF

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Members of the Paracoccidioides complex are the causative agents of Paracoccidioidomycosis (PCM), a human systemic mycosis endemic in Latin America. Upon initial contact with the host, the pathogen needs to uptake micronutrients. Nitrogen is an essential source for biosynthetic pathways. Adaptation to nutritional stress is a key feature of fungi in host tissues. Fungi utilize nitrogen sources through Nitrogen Catabolite Repression (NCR). NCR ensures the scavenging, uptake and catabolism of alternative nitrogen sources, when preferential ones, such as glutamine or ammonium, are unavailable. The NanoUPLC-MSE proteomic approach was used to investigate the NCR response of Paracoccidioides lutzii after growth on proline or glutamine as a nitrogen source. A total of 338 differentially expressed proteins were identified. P. lutzii demonstrated that gluconeogenesis, β-oxidation, glyoxylate cycle, adhesin-like proteins, stress response and cell wall remodeling were triggered in NCR-proline conditions. In addition, within macrophages, yeast cells trained under NCR-proline conditions showed an increased ability to survive. In general, this study allows a comprehensive understanding of the NCR response employed by the fungus to overcome nutritional starvation, which in the human host is represented by nutritional immunity. In turn, the pathogen requires rapid adaptation to the changing microenvironment induced by macrophages to achieve successful infection.

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Section: Discussionmentioning

confidence: 96%

Proteomics of Paracoccidioides lutzii: Overview of Changes Triggered by Nitrogen Catabolite Repression

Cruz-Leite,

Moreira,

Silva

et al. 2023

JoF

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“…The transcript and protein levels are elevated on urea media. The urease deficient mutant displays attenuated virulence, and its spores are more susceptible to macrophage-mediated killing [28] .We can hypothesize that elevated blood urea nitrogen levels may facilitate the growth of Aspergillus spores in the body and prevent them from being phagocytized by macrophages, leading to IPA. However, this requires further experimentation to be proven.…”

Section: Discussionmentioning

confidence: 99%

A nomogram model in invasive pulmonary aspergillosis diagnosis based on a retrospective study

Qian,

Yang,

Wang

et al. 2023

Preprint

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Backgroud:With the easing of governmental COVID-19 restrictions, an upward trend was found for Aspergillus isolation in hospitalized patients . Objectives:Our research aims to analyze the clinical significance of Aspergillus positivity in respiratory tract samples and construct a diagnostic model in clinical practice. Methods: We retrospectively analyzed Aspergillus-positive patients in the three time periods before and after the relaxation of COVID-19 measures. Patients were admitted in into death or survival group to analyze independent risk factors for mortality. Based on the current standards, we divided patients into Invasive pulmonary aspergillosis( IPA) group and colonization group, in an attempt to identify the risk factors for IPA.The independent risk factors of death and IPA were determined through logistic regression analysis.A nomogram model was constructed to evaluate the predictive value of risk factors in IPA diagnosis.Mann–Whitney U test was used to compare the differences between the laboratory indicators of the IPA and the colonization. Resluts: There were 60% (125/208）patients with COVID-19 infection. We found that the overall in-hospital mortality rate was 33.6% (70/208). IPA (p<0.001), old age (p=0.011), mechanical ventilation requirement (p<0.001),and corticosteroids expose (p=0.002) were independent risk factors for mortality, while antifungal treatment had a protective effect (p<0.037).The proportion of IPA in death and survival group were 80% and 48%(p<0.001), respectively.The nomogram was established based on respiratory tract bronchial disease , recurring fever, the use of at least two types of antibiotics, and number of positive Aspergillus culture has significant diagnostic value for IPA(AUC:0.813,sensitivity0.823,specificity:0.714) .Moreover, there were statistical differences between the IPA and colonization group in serum GM level, BDG level, neutrophil absolute value ,blood glucose level , and blood urea nitrogen level(BUN). Conclusion:Due to the rapid progression and high mortality rate of IPA, Aspergillus positivity in respiratory tract samples should be cause for concern.In our study,we created a nomogram model in invasive pulmonary aspergillosis diagnosis. When patients with underlying respiratory diseases , recurring fever and use different types of antibiotics, it is best to monitor of laboratory indicators, such as cultures,GM and BDG tests .If there is a high clinical suspicion, we recommend starting empirical treatment with triazole drugs.

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“…It is noted that most of Nitrospira genomes lack ureE that serves as a bridge to acquire nickel from hydrogenase maturation factor HypA, which is subsequently donated to UreG. HypA is a metallochaperone and selectively delivers the nickel to the active site ( Xiong et al, 2023 ). The absence of ureE may result in low urease activity in NOB ( Carter et al, 2009 ; Fujitani et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Genomic insight into strategy, interaction and evolution of nitrifiers in metabolizing key labile-dissolved organic nitrogen in different environmental niches

Liu,

Chen,

2023

Front. Microbiol.

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Ammonia-oxidizing archaea (AOA) and bacteria (AOB), nitrite-oxidizing bacteria (NOB), and complete ammonia oxidizers (comammox) are responsible for nitrification in nature; however, some groups have been reported to utilize labile-dissolved organic nitrogen (LDON) for satisfying nitrogen demands. To understand the universality of their capacity of LDON metabolism, we collected 70 complete genomes of AOA, AOB, NOB, and comammox from typical environments for exploring their potentials in the metabolism of representative LDON (urea, polyamines, cyanate, taurine, glycine betaine, and methylamine). Genomic analyses showed that urea was the most popular LDON used by nitrifiers. Each group harbored unique urea transporter genes (AOA: dur3 and utp, AOB: utp, and NOB and comammox: urtABCDE and utp) accompanied by urease genes ureABC. The differentiation in the substrate affinity of these transporters implied the divergence of urea utilization efficiency in nitrifiers, potentially driving them into different niches. The cyanate transporter (cynABD and focA/nirC) and degradation (cynS) genes were detected mostly in NOB, indicating their preference for a wide range of nitrogen substrates to satisfy high nitrogen demands. The lack of genes involved in the metabolism of polyamines, taurine, glycine betaine, and methylamines in most of nitrifiers suggested that they were not able to serve as a source of ammonium, only if they were degraded or oxidized extracellularly as previously reported. The phylogenetic analyses assisted with comparisons of GC% and the Codon Adaptation Index between target genes and whole genomes of nitrifiers implied that urea metabolic genes dur3 and ureC in AOA evolved independently from bacteria during the transition from Thaumarchaeota to AOA, while utp in terrestrial AOA was acquired from bacteria via lateral gene transfer (LGT). Cyanate transporter genes cynS and focA/nirC detected only in a terrestrial AOA Candidadus Nitrsosphaera gargensis Ga9.2 could be gained synchronously with Nitrospira of NOB by an ancient LGT. Our results indicated that LDON utilization was a common feature in nitrifiers, but metabolic potentials were different among nitrifiers, possibly being intensely interacted with their niches, survival strategies, and evolutions.

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Urease of Aspergillus fumigatus Is Required for Survival in Macrophages and Virulence

Abstract: The development of antifungal drugs is an urgent task, but it has proven to be difficult due to many similarities between fungal and animal cells. Here, we characterized the urease system in A. fumigatus , which depends on nickel for activity.

Cited by 7 publications

References 80 publications

Proteomics of Paracoccidioides lutzii: Overview of Changes Triggered by Nitrogen Catabolite Repression

Proteomics of Paracoccidioides lutzii: Overview of Changes Triggered by Nitrogen Catabolite Repression

A nomogram model in invasive pulmonary aspergillosis diagnosis based on a retrospective study

Genomic insight into strategy, interaction and evolution of nitrifiers in metabolizing key labile-dissolved organic nitrogen in different environmental niches

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