scholarly journals N-Acetylglucosamine-Induced Cell Death in Candida albicans and Its Implications for Adaptive Mechanisms of Nutrient Sensing in Yeasts

mBio ◽  
2015 ◽  
Vol 6 (5) ◽  
Author(s):  
Han Du ◽  
Guobo Guan ◽  
Xiaoling Li ◽  
Megha Gulati ◽  
Li Tao ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Death ◽  
Candida Albicans ◽  
Fungal Pathogen ◽  
Reactive Oxygen ◽  
Nutrient Sensing ◽  
Oxygen Species ◽  
Gi Tract ◽  
Content Type ◽  
Cell Death Pathway

ABSTRACT Single-celled organisms have different strategies to sense and utilize nutrients in their ever-changing environments. The opportunistic fungal pathogen Candida albicans is a common member of the human microbiota, especially that of the gastrointestinal (GI) tract. An important question concerns how C. albicans gained a competitive advantage over other microbes to become a successful commensal and opportunistic pathogen. Here, we report that C. albicans uses N-acetylglucosamine (GlcNAc), an abundant carbon source present in the GI tract, as a signal for nutrient availability. When placed in water, C. albicans cells normally enter the G0 phase and remain viable for weeks. However, they quickly lose viability when cultured in water containing only GlcNAc. We term this phenomenon GlcNAc-induced cell death (GICD). GlcNAc triggers the upregulation of ribosomal biogenesis genes, alterations of mitochondrial metabolism, and the accumulation of reactive oxygen species (ROS), followed by rapid cell death via both apoptotic and necrotic mechanisms. Multiple pathways, including the conserved cyclic AMP (cAMP) signaling and GlcNAc catabolic pathways, are involved in GICD. GlcNAc acts as a signaling molecule to regulate multiple cellular programs in a coordinated manner and therefore maximizes the efficiency of nutrient use. This adaptive behavior allows C. albicans’ more efficient colonization of the gut. IMPORTANCE The ability to rapidly and appropriately respond to nutrients in the environment is crucial to free-living microorganisms. To maximize the use of available nutrients, microorganisms often use a limiting nutritional component as a signal to coordinate multiple biological processes. The human fungal pathogen Candida albicans uses N-acetylglucosamine (GlcNAc) as a signal for the availability of external nutrient resources. GlcNAc induces rapid cell death in C. albicans due to the constitutive activation of oxidative metabolism and accumulation of reactive oxygen species (ROS), and multiple pathways are involved in its regulation. This study sheds light on the mechanisms of niche specialization of pathogenic fungi and raises the possibility that this cell death pathway could be an unexplored therapeutic target.

scholarly journals Reactive oxygen species as transducers of sphinganine-mediated cell death pathway

2011 ◽  
Vol 6 (10) ◽  
pp. 1616-1619 ◽  
Author(s):  
Mariana Saucedo-García ◽  
Ariadna González-Solís ◽  
Priscila Rodríguez-Mejía ◽  
Teresa de Jesús Olivera-Flores ◽  
Sonia Vázquez-Santana ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Death ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Cell Death Pathway

scholarly journals Candida albicans Triggers NLRP3-Mediated Pyroptosis in Macrophages

2013 ◽  
Vol 13 (2) ◽  
pp. 329-340 ◽  
Author(s):  
Melanie Wellington ◽  
Kristy Koselny ◽  
Fayyaz S. Sutterwala ◽  
Damian J. Krysan
Keyword(s):  
Cell Death ◽  
Candida Albicans ◽  
Fungal Pathogen ◽  
Matched Control ◽  
Intracellular Pathogen ◽  
Content Type ◽  
Caspase 1 ◽  
Cell Death Pathway ◽  
Cellular Integrity ◽  
Pharmacologic Inhibition

ABSTRACTPyroptosis is an inflammasome-mediated programmed cell death pathway triggered in macrophages by a variety of stimuli, including intracellular bacterial pathogens. Activation of pyroptosis leads to the secretion of interleukin-1β (IL-1β) and pore-mediated cell lysis. Although not considered an intracellular pathogen,Candida albicansis able to kill and, thereby, escape from macrophages. Here, we show thatC. albicans-infected bone marrow-derived macrophages (BMDM) and murine J774 macrophages undergo pyroptotic cell death that is suppressed by glycine and pharmacologic inhibition of caspase-1. Infection of BMDM harvested from mice lacking components of the inflammasome revealed that pyroptosis was dependent on caspase-1, ASC, and NLRP3 and independent of NLRC4. In contrast to its role during intracellular bacterial infection, pyroptosis does not restrictC. albicansreplication. NonfilamentousCandidaspp. did not trigger pyroptosis, whileCandida krusei, which forms pseudohyphae in macrophages, triggered much lower levels than didC. albicans. Interestingly, aSaccharomyces cerevisiaestrain from the filamentous background Σ1278 also triggered low, but significant, levels of pyroptosis. We have found that deletion of the transcription factorUPC2decreases pyroptosis but has little effect on filamentation in the macrophage. In addition, a gain-of-function mutant ofUPC2induces higher levels of pyroptosis than does a matched control strain. Taken together, these data are most consistent with a model in which filamentation is necessary but not sufficient to trigger NLRP3 inflammasome-mediated pyroptosis. This is the first example of a fungal pathogen triggering pyroptosis and indicates thatC. albicans-mediated macrophage damage is not solely due to hypha-induced physical disruption of cellular integrity.

scholarly journals Candida albicans Induces Arginine Biosynthetic Genes in Response to Host-Derived Reactive Oxygen Species

2012 ◽  
Vol 12 (1) ◽  
pp. 91-100 ◽  
Author(s):  
Claudia Jiménez-López ◽  
John R. Collette ◽  
Kimberly M. Brothers ◽  
Kelly M. Shepardson ◽  
Robert A. Cramer ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Candida Albicans ◽  
Amino Acid ◽  
Reactive Oxygen ◽  
Single Amino Acid ◽  
Dependent Manner ◽  
Oxygen Species ◽  
Biosynthetic Genes ◽  
Content Type

ABSTRACTThe interaction ofCandida albicanswith phagocytes of the host's innate immune system is highly dynamic, and its outcome directly impacts the progression of infection. While the switch to hyphal growth within the macrophage is the most obvious physiological response, much of the genetic response reflects nutrient starvation: translational repression and induction of alternative carbon metabolism. Changes in amino acid metabolism are not seen, with the striking exception of arginine biosynthesis, which is upregulated in its entirety during coculture with macrophages. Using single-cell reporters, we showed here that arginine biosynthetic genes are induced specifically in phagocytosed cells. This induction is lower in magnitude than during arginine starvationin vitroand is driven not by an arginine deficiency within the phagocyte but instead by exposure to reactive oxygen species (ROS). Curiously, these genes are induced in a narrow window of sublethal ROS concentrations.C. albicanscells phagocytosed by primary macrophages deficient in thegp91phoxsubunit of the phagocyte oxidase do not express theARGpathway, indicating that the induction is dependent on the phagocyte oxidative burst.C. albicans argpathway mutants are retarded in germ tube and hypha formation within macrophages but are not notably more sensitive to ROS. We also find that theARGpathway is regulated not by the general amino acid control response but by transcriptional regulators similar to theSaccharomyces cerevisiaeArgR complex. In summary, phagocytosis induces this single amino acid biosynthetic pathway in an ROS-dependent manner.

scholarly journals SrrAB Modulates Staphylococcus aureus Cell Death through Regulation ofcidABCTranscription

2016 ◽  
Vol 198 (7) ◽  
pp. 1114-1122 ◽  
Author(s):  
Ian H. Windham ◽  
Sujata S. Chaudhari ◽  
Jeffrey L. Bose ◽  
Vinai C. Thomas ◽  
Kenneth W. Bayles
Keyword(s):  
Reactive Oxygen Species ◽  
Staphylococcus Aureus ◽  
Cell Death ◽  
Reactive Oxygen ◽  
Extracellular Dna ◽  
Death Process ◽  
Oxygen Species ◽  
Content Type ◽  
Biofilm Development

ABSTRACTThe death and lysis of a subpopulation inStaphylococcus aureusbiofilm cells are thought to benefit the surviving population by releasing extracellular DNA, a critical component of the biofilm extracellular matrix. Although the means by whichS. aureuscontrols cell death and lysis is not understood, studies implicate the role of thecidABCandlrgABoperons in this process. Recently, disruption of thesrrABregulatory locus was found to cause increased cell death during biofilm development, likely as a result of the sensitivity of this mutant to hypoxic growth. In the current study, we extended these findings by demonstrating that cell death in the ΔsrrABmutant is dependent on expression of thecidABCoperon. The effect ofcidABCexpression resulted in the generation of increased reactive oxygen species (ROS) accumulation and was independent of acetate production. Interestingly, consistently with previous studies,cidC-encoded pyruvate oxidase was found to be important for the generation of acetic acid, which initiates the cell death process. However, these studies also revealed for the first time an important role of thecidBgene in cell death, as disruption ofcidBin the ΔsrrABmutant background decreased ROS generation and cell death in acidC-independent manner. ThecidBmutation also caused decreased sensitivity to hydrogen peroxide, which suggests a complex role for this system in ROS metabolism. Overall, the results of this study provide further insight into the function of thecidABCoperon in cell death and reveal its contribution to the oxidative stress response.IMPORTANCEThe manuscript focuses on cell death mechanisms inStaphylococcus aureusand provides important new insights into the genes involved in this ill-defined process. By exploring the cause of increased stationary-phase death in anS. aureusΔsrrABregulatory mutant, we found that the decreased viability of this mutant was a consequence of the overexpression of thecidABCoperon, previously shown to be a key mediator of cell death. These investigations highlight the role of thecidBgene in the death process and the accumulation of reactive oxygen species. Overall, the results of this study are the first to demonstrate a positive role for CidB in cell death and to provide an important paradigm for understanding this process in all bacteria.

Apigenin drives the production of reactive oxygen species and initiates a mitochondrial mediated cell death pathway in prostate epithelial cells

The Prostate ◽  
2005 ◽  
Vol 63 (2) ◽  
pp. 131-142 ◽  
Author(s):  
Colm Morrissey ◽  
Amanda O'Neill ◽  
Barbara Spengler ◽  
Volker Christoffel ◽  
John M. Fitzpatrick ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Death ◽  
Epithelial Cells ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Cell Death Pathway ◽  
Prostate Epithelial Cells

Amplification of the γ-irradiation-induced cell death pathway by reactive oxygen species in human U937 cells

2008 ◽  
Vol 20 (5) ◽  
pp. 916-924 ◽  
Author(s):  
Eun Mi Kim ◽  
Hyun Sook Yang ◽  
Sung Wook Kang ◽  
Jin-Nyoung Ho ◽  
Seung Bum Lee ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Death ◽  
Reactive Oxygen ◽  
U937 Cells ◽  
Oxygen Species ◽  
Γ Irradiation ◽  
Cell Death Pathway

scholarly journals Natural Variation in Clinical Isolates of Candida albicans Modulates Neutrophil Responses

mSphere ◽  
2020 ◽  
Vol 5 (4) ◽  
Author(s):  
Madhu Shankar ◽  
Tricia L. Lo ◽  
Ana Traven
Keyword(s):  
Reactive Oxygen Species ◽  
Candida Albicans ◽  
Reactive Oxygen ◽  
Neutrophil Extracellular Traps ◽  
Prototype Strain ◽  
Human Neutrophils ◽  
Oxygen Species ◽  
Content Type ◽  
Extracellular Traps ◽  
Strain Sc5314

ABSTRACT Neutropenia predisposes patients to life-threatening infection with Candida albicans, a commensal and opportunistic fungal pathogen. How phenotypic variation in C. albicans isolates dictates neutrophil responses is poorly understood. By using a panel of clinical C. albicans strains, here we report that the prototype strain SC5314 induces the most potent accumulation of reactive oxygen species (ROS) and neutrophil extracellular traps (NETs) by human neutrophils of all tested isolates. ROS and NET accumulation positively correlated with the degree of hyphal formation by the isolates, the hypha being the fungal morphotype that promotes pathogenesis. However, there was no correlation of ROS and NET accumulation with fungal killing by neutrophils. Fungal killing was also not correlated with phagocytosis levels or oxidative stress susceptibility of the isolates. The bloodstream isolate P94015 cannot make hyphae and was previously shown to be hyperfit in the murine gut commensalism model. Our results show that P94015 displays poor phagocytosis by neutrophils, the least ROS and NET accumulation of all tested isolates, and resistance to neutrophil-mediated killing. Our data suggest that reduced susceptibility to neutrophils is likely to be independent from a previously described genetic mutation in P94015 that promotes commensalism. Reduced clearance by neutrophils could benefit commensal fitness of C. albicans and could also have promoted the virulence of P94015 in the human patient in the absence of hyphal morphogenesis. Collectively, our study provides new insights into neutrophil interactions with C. albicans and suggests that studying diverse isolates informs knowledge of the relevant aspects of this key immune interaction. IMPORTANCE Neutrophils are the key immune cell type for host defenses against infections with Candida albicans. C. albicans strains isolated from patients display large phenotypic diversity, but how this diversity impacts host-pathogen interactions with neutrophils is incompletely defined. Here, we show that important neutrophil responses, such as accumulation of reactive oxygen species and neutrophil extracellular traps, as well as the levels of phagocytosis and killing of the pathogen, differ when comparing diverse C. albicans isolates. A bloodstream patient isolate previously described as more suited to commensalism than pathogenesis in animal models is relatively “silent” to neutrophils and resistant to killing. Our findings illuminate the relationships between fungal morphogenesis, neutrophil responses, and C. albicans survival. Our findings suggest that host phenotypes of a commensally adapted strain could be driven by resistance to immune clearance and indicate that we should extend our studies beyond the “prototype” strain SC5314 for deeper understanding of Candida-neutrophil interactions.

scholarly journals Reactive oxygen species activate a Ca2+-dependent cell death pathway in the unicellular organism Trypanosoma brucei brucei

1999 ◽  
Vol 340 (1) ◽  
pp. 33-40 ◽  
Author(s):  
Evelyn L. RIDGLEY ◽  
Zhao-hui XIONG ◽  
Larry RUBEN
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Death ◽  
Trypanosoma Brucei ◽  
Reactive Oxygen ◽  
Cell Permeability ◽  
Death Process ◽  
Oxygen Species ◽  
Trypanosoma Brucei Brucei ◽  
Acetoxymethyl Ester ◽  
Cell Death Pathway

Here we examine a cell death process induced by reactive oxygen species (ROS) in the haemoflagellate Trypanosoma brucei brucei. Ca2+ distribution in cellular compartments was measured with stable transformants expressing aequorin targeted to the cytosol, nucleus or mitochondrion. Within 1.5 h of ROS production, mitochondrial Ca2+ transport was impaired and the Ca2+ barrier between the nuclear envelope and cytosol was disrupted. Consequently the mitochondrion did not accumulate Ca2+ efficiently in response to an extracellular stimulus, and excess Ca2+ accumulated in the nucleus. The terminal transferase deoxytidyl uridine end labelling assay revealed that, 5 h after treatment with ROS, extensive fragmentation of nuclear DNA occurred in over 90% of the cells. Permeability changes in the plasma membrane did not occur until an additional 2 h had elapsed. The intracellular Ca2+ buffer, EGTA acetoxymethyl ester, prevented DNA fragmentation and prolonged the onset of changes in cell permeability. Despite some similarities to apoptosis, nuclease activation was not a consequence of caspase 3, caspase 1, calpain, serine protease, cysteine protease or proteasome activity. Moreover, trypanosomes expressing mouse Bcl-2 were not protected from ROS even though protection from mitochondrial dysfunction and ROS have been reported for mammalian cells. Overall, these results demonstrate that Ca2+ pathways can induce pathology in trypanosomes, although the specific proteins involved might be distinct from those in metazoans.

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