Microevolution of Cryptococcus neoformans in high CO2 converges on mutations isolated from patients with relapsed cryptococcosis
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PROVIDER: PRJNA1200720 | ENA |
REPOSITORIES: ENA
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Project description:Cryptococcus neoformans is an environmental fungus that causes an estimated 180,000 deaths annually and transitions from the external environment to the host environment to cause disease. CO2 concentrations in the atmosphere (0.04%) are dramatically lower than in mammalian tissues (5%). Environmental C. neoformans strains that cannot tolerate 5% CO2 are much less virulent than CO2-tolerant strains. Microevolution at elevated CO2generated loss-of-function mutations in the nucleotide binding protein Avc1 that confer CO2 tolerance to CO2-intolerant strains. Mechanistically, Avc1 positively regulates the expression of plasma membrane transporters including PDR9, a phospholipid floppase that negatively modulates CO2 fitness. Deletion of AVC1 in five CO2-intolerant environmental strains increased competitive fitness in host CO2 and in a mouse infection model. Importantly, strains with similar AVC1 mutations have emerged in patients with relapsed cryptococcosis. Therefore, this microevolutionary convergence strongly suggests that adaptation to host CO2 is a significant driver of C. neoformans fitness during infection.
2025-02-24 | GSE284927 | GEO
Project description:Cryptococcal osteomyelitis is an infrequent infection which is usually associated with disseminated cryptococcosis or underlying immunocompromised conditions. Here we described a rare case with isolated iliac cryptococcosis in an immunocompetent patient. Through histological, microbial, and molecular biological examinations, the pathogen was finally identified as C. neoformans VNI genotype, which likely originated from environmental bird droppings. The clinical isolate was hypomelanized but fully virulent in mouse infection model. The patient displayed lower CD4+-T lymphocyte ratio, reduced serum IFN-γ and IL-12, and dysregulated transcriptional profile of blood leukocytes compare with healthy host. After surgical excision and 34 weeks’ antifungal treatment, the patient got clinical cured. Our study suggested that cryptococcosis development was closely associated with the interaction of fungal agent and host immunity. Accurate diagnosis of bone cryptococcosis depends mainly on histological and fungal examinations. A combination of antifungal agent treatment regimen and surgery were quite effective for resolving bone cryptococcosis.
2018-04-17 | GSE108534 | GEO
Project description:Cryptococcus neoformans is a ubiquitous free-living soil yeast and opportunistic pathogen that causes ~223,100 cases of cryptococcal meningitis per year, killing over 180,000 people. The pathogenicity of C. neoformans relies on its adaptation to the host conditions. An important difference between its natural environment and the mammalian host is the concentration of CO2. CO2 levels in the host fluctuate around 5%, which is ~125-fold higher than in ambient air. We recently found that while clinical isolates are tolerant to host levels ofCO2, many environmental isolates are CO2-sensitive and virulence-attenuated in animal models. The genetic basis responsible for cryptococcal adaptation to high levels of CO2 is unknown. Here, we utilized quantitative trait loci (QTL) mapping with 374 progeny from a cross between a CO2-tolerant clinical isolate and a CO2-sensitive environmental isolate to identify genetic regions regulating CO2 tolerance. To identify specific quantitative trait genes (QTGs), we applied fine mapping through backcrossing and bulk segregant analysis coupled with pooled genome sequencing of near-isogenic progeny but with distinct tolerance levels to CO2. The roles of the identified QTGs in CO2 tolerance were verified by targeted gene deletion. We further demonstrated that virulence levels among near-isogenic strains in a murine model of cryptococcosis correlate with their levels of CO2 tolerance. Moreover, we discovered that sensitive strains may adapt in vivo to become more tolerant to increased CO2 levels and more virulent. These findings highlight the underappreciated role of the host CO2 tolerance and its importance in the ability of an opportunistic environmental pathogen to cause disease.
2024-08-09 | GSE260932 | GEO
Project description:Elevation of arginase enzyme activity in the lung contributes to the pathogenesis of various chronic inflammatory diseases and infections. Inhibition of arginase expression and activity is able to alleviate those effects. Here, we investigated the immunomodulatory effect of arginase inhibitor in C. neoformans infection. In the pulmonary cryptococcosis model that was shown to recapitulate human infection, we found arginase expression was excessively induced in the lung during the late stage of infection. To inhibit the activity of arginase, we administered a specific arginase inhibitor, nor-NOHA, during C. neoformans infection. Inhibition of arginase reduced eosinophil infiltration and level of IL-13 secretion in the lungs. Whole lung transcriptome RNA-sequencing analysis revealed that treatment with nor-NOHA resulted in shifting the Th2-type gene expression patterns induced by C. neoformans infection to the Th1-type immune profile, with higher expression of cytokines Ifng, Il6, Tnfa, Csf3, chemokines Cxcl9 and Cxcl10 and transcription factor Stat1. More importantly, mice treated with arginase inhibitor had more infiltrating brain leukocytes and enhanced gene expression of Th1-associated cytokines and chemokines that are known to be essential for protection against C. neoformans infection. Inhibition of arginase dramatically attenuated spleen and brain infection, with improved survival. Taken together, these studies demonstrated that inhibiting arginase activity induced by C. neoformans infection can modulate host immune response by enhancing protective type-1 immune response during C. neoformans infection. The inhibition of arginase activity could be an immunomodulatory target to enhance protective anti-cryptococcal immune responses.
2024-04-06 | GSE255160 | GEO
Project description:Paradoxical cryptococcosis-associated immune reconstitution inflammatory syndrome
2019-01-29 | GSE108649 | GEO
Project description:Carbon dioxide (CO2) sensing, transport, and metabolism play a pivotal role in survival and proliferation of pathogenic microbes infecting human host from natural environments due to the drastic difference of CO2 levels. Carbonic anhydrases (CAs) are not only key CO2-metabolic enzymes catalyzing reversible interconversion between CO2 and bicarbonate (HCO3-), but also important CO2-signaling modulators. Cryptococcus neoformans that causes fatal fungal meningitis contains two functional CAs, Can1 and Can2, among which Can2 plays essential roles for growth and sexual differentiation of the pathogen. However, downstream genes and signaling network regulated by CAs have not been studied thus far. In this study, we constructed a C. neoformans strain where CAN2 expression is controlled by the CTR4 (copper transporter) promoter and elucidated its transcriptome patterns by using DNA microarray analysis to elucidate downstream target genes of Can2. Expectedly, the CAN2 promoter replacement strain showed growth defects in a CO2-dependent manner when CAN2 is repressed. The CA-transcriptome analysis discovered a number of Can2-dependent genes, including those involved in fatty acid biosynthesis (FAS1), sexual differentiation (GPB1), capsule structure organization (CAS3), iron-metabolism (CFO2), and a number of stress-regulated genes, including an oxidative stress-responsive Atf1 transcription factor, although a majority of them do not have any orthologs in other fungi. The present study revealed other roles of Atf1 in capsule and melanin production and diverse stress responses, including thermotolerance and antifungal drug resistance, of C. neoformans. This study provides further insights into the signaling network of CA/CO2-sensing pathway in pathogenic fungi.
2010-06-01 | GSE21192 | GEO
Project description:Constraints on the rate of protein sequence evolution have been a central question in evolutionary biology. Orthology analysis between closely related species has revealed that the evolutionary speed is constrained by the expression level, with highly expressed proteins evolving slowly. This negative correlation between expression levels and evolutionary rates (known as the E-R anticorrelation) has already been widely observed in past macroevolution between species, for example, between Escherichia coli and Salmonella. However, it remains unclear whether this seemingly general law also governs microevolution, including past and de novo, within a species. To explore the ubiquitous impact of expression level on molecular evolution in bacteria, we analysed genome sequences for 99 strains of E. coli for microevolution in nature. We also analysed genomic mutations accumulated under laboratory conditions as a model of de novo microevolution. Here, we show that the E-R anticorrelation is significant in both past microevolution and de novo evolution in E. coli. Our data also indicate that purifying selection acting on highly expressed genes contributes to the ubiquity of the E-R anticorrelation. This study confirmed ongoing purifying selection acting on highly expressed genes, and implied that expression level has a ubiquitous impact on the speed of molecular diversification evolution in bacteria.
2022-09-01 | GSE189008 | GEO
Project description:Following antifungal treatment, Candida albicans, and other human pathogenic fungi can undergo microevolution, which leads to the emergence of drug resistance. However, the capacity for microevolutionary adaptation of fungi goes beyond the development of drug resistance. Here we used an experimental microevolution approach to show that one of the central pathogenicity mechanisms of C. albicans, the yeast-to-hyphae transition, can be subject to experimental evolution. The C. albicans cph1Δ/efg1Δ mutant is non-filamentous, as central signalling pathways linking environmental cues to hypha formation are disrupted. We subjected this mutant to constant selection pressure in the hostile environment of the macrophage phagosome. In a comparatively short time-frame, the mutant evolved the ability to escape macrophages by filamentation. To investigate the transcriptional response underlying the yeast-to-filament transition in the evolved strain, we applied RNA-Seq technology. Furthermore, RNA-Seq data were used to identify SNPs, which are specific for the evolved strain.
2015-03-31 | GSE56174 | GEO
Project description:Cyanobacteria are oxygenic photoautotrophs notable for their ability to utilize atmospheric CO2 as the major source of carbon. The prospect of using cyanobacteria in converting solar energy and high concentrations of CO2 (e.g. flue gas from coal power plants) efficiently into biomass and renewable energy sources is of interest to many research fields. In order to guide further advances in this area, a better understanding about the metabolic changes that occur under conditions of high CO2 is important. The objective of this study is to utilize genome-wide microarray expression profiling in the unicellular diazotrophic cyanobacterium Cyanothece 51142 grown in 8% CO2-enriched air and to determined the impact of high CO2 on cyanobacterial cell physiology and growth.
2012-10-30 | GSE37621 | GEO
Project description:MicroEvolution study of Mycobacterium tuberculosis
| PRJNA52637 | ENA