scholarly journals Heme Competition Triggers an Increase in the Pathogenic Potential of Porphyromonas gingivalis in Porphyromonas gingivalis-Candida albicans Mixed Biofilm

2020 ◽  
Vol 11 ◽  
Author(s):  
Yanyang Guo ◽  
Yu Wang ◽  
Yijin Wang ◽  
Yabing Jin ◽  
Chen Wang
Keyword(s):  
Candida Albicans ◽  
Porphyromonas Gingivalis ◽  
Morphological Changes ◽  
Single Species ◽  
Healthy Human ◽  
Pathogenic Potential ◽  
Expression Of Genes ◽  
Gene Level ◽  
Genes Encoding ◽  
Laser Confocal Microscope

As one of the main pathogens of periodontitis, Porphyromonas gingivalis often forms mixed biofilms with other bacteria or fungi under the gingiva, such as Candida albicans. Heme is an important iron source for P. gingivalis and C. albicans that supports their growth in the host. From the perspective of heme competition, this study aims to clarify that the competition for heme enhances the pathogenic potential of P. gingivalis during the interaction between P. gingivalis and C. albicans. Porphyromonas gingivalis single-species biofilm and P. gingivalis-C. albicans dual-species biofilm were established in a low- and high-heme environment. The results showed that the vitality of P. gingivalis was increased in the dual-species biofilm under the condition of low heme, and the same trend was observed under a laser confocal microscope. Furthermore, the morphological changes in P. gingivalis were observed by electron microscope, and the resistance of P. gingivalis in dual-species biofilm was stronger against the killing effect of healthy human serum and antibiotics. The ability of P. gingivalis to agglutinate erythrocyte was also enhanced in dual-species biofilm. These changes disappeared when heme was sufficient, which confirmed that heme competition was the cause of thepathogenicy change in P. gingivalis. Gene level analysis showed that P. gingivalis was in a superior position in the competition relationship by increasing the expression of heme utilization-related genes, such as HmuY, HmuR, HusA, and Tlr. In addition, the expression of genes encoding gingipains (Kgp, RgpA/B) was also significantly increased. They not only participate in the process of utilizing heme, but also are important components of the virulence factors of P. gingivalis. In conclusion, our results indicated that the pathogenic potential of P. gingivalis was enhanced by C. albicans through heme competition, which ultimately promoted the occurrence and development of periodontitis and, therefore, C. albicans subgingival colonization should be considered as a factor in assessing the risk of periodontitis.

scholarly journals Expression of the apoptosis-releated genes in patients with newly diagnosed chronic lymphocytic leukemia in clinical data context

2018 ◽  
Vol 17 (2) ◽  
pp. 41-46 ◽  
Author(s):  
S. G. Zakharov ◽  
A. K. Golenkov ◽  
A. V. Misyurin ◽  
E. V. Kataeva ◽  
A. A. Rudakova ◽  
...  
Keyword(s):  
Gene Expression ◽  
Clinical Manifestations ◽  
Multivariate Regression Analysis ◽  
Lymphocytic Leukemia ◽  
Newly Diagnosed ◽  
Expression Of Genes ◽  
Gene Level ◽  
Genes Encoding ◽  
Group Ii ◽  
High Level

Introduction.The given data of fundamental studies of apoptosis processes in B-cell lymphocytic leukemia (B-CLL) testifies about the complexity and variety of mechanisms affecting the kinetics of normal cells and tumor lymphocytes in this disease. It is important to study the severity of clinical manifestations of the disease depending on the expression of the genes that modulate apoptosis.The purposeof the study is to compare the activity of genes encoding apoptosis modulators, the cell cycle and cancer-testicular PRAME protein with clinical manifestations of the disease in primary patients with B-CLL.Materials and methods.The level of expression of the proapoptotic genes FAS, TRAIL, TNFR2, DR4/5 and DR3, as well as the HSP27, XIAP genes, blocking apoptosis was determined in 23 patients with newly diagnosed chronic B-CLL. In addition, expression of genes TP53 and P21 and cancer-testis gene PRAME are tested.Results.According to the multivariate regression analysis, the FAS gene expression in the onset of the disease had the greatest impact on the clinical characteristics of the disease. In this connection, the patients were divided into groups with normal (group) and low gene level (group II). A low level of FAS expression (Me 387 %) was associated with stage II disease (p = 0.03), a large number of lympho cytes (p = 0.001), fewer erythrocytes (p = 0.08), and a lower level of TNFR2 gene expression (p = 0.08), high level of expression of XIAP, HSP27, P21. Overall, the anti-apoptotic potential in Group II patients was higher, which was accompanied by more pronounced clinical manifestations of the disease.Conclusions.The increased anti-apoptotic potential of tumor lymphocytes in newly diagnosed B-CLL is accompanied by a larger tumor mass and greater clinical and hematological manifestation of the disease.

scholarly journals Mds3 Regulates Morphogenesis in Candida albicans through the TOR Pathway

2010 ◽  
Vol 30 (14) ◽  
pp. 3695-3710 ◽  
Author(s):  
Lucia F. Zacchi ◽  
Jonatan Gomez-Raja ◽  
Dana A. Davis
Keyword(s):  
Candida Albicans ◽  
Ribosomal Proteins ◽  
Ph Sensing ◽  
Tor Pathway ◽  
Preferential Expression ◽  
Human Fungal Pathogen ◽  
Expression Of Genes ◽  
Mucosal Surfaces ◽  
Genes Encoding ◽  
Morphological Defects

ABSTRACT The success of Candida albicans as a major human fungal pathogen is dependent on its ability to colonize and survive as a commensal on diverse mucosal surfaces. One trait required for survival and virulence in the host is the morphogenetic yeast-to-hypha transition. Mds3 was identified as a regulator of pH-dependent morphogenesis that functions in parallel with the classic Rim101 pH-sensing pathway. Microarray analyses revealed that mds3Δ/Δ cells had an expression profile indicative of a hyperactive TOR pathway, including the preferential expression of genes encoding ribosomal proteins and a decreased expression of genes involved in nitrogen source utilization. The transcriptional and morphological defects of the mds3Δ/Δ mutant were rescued by rapamycin, an inhibitor of TOR, and this rescue was lost in strains carrying the rapamycin-resistant TOR1-1 allele or an rbp1Δ/Δ deletion. Rapamycin also rescued the transcriptional and morphological defects associated with the loss of Sit4, a TOR pathway effector, but not the loss of Rim101 or Ras1. The sit4Δ/Δ and mds3Δ/Δ mutants had additional phenotypic similarities, suggesting that Sit4 and Mds3 function similarly in the TOR pathway. Finally, we found that Mds3 and Sit4 coimmunoprecipitate. Thus, Mds3 is a new member of the TOR pathway that contributes to morphogenesis in C. albicans as a regulator of this key morphogenetic pathway.

scholarly journals PgRsp Is a Novel Redox-Sensing Transcription Regulator Essential for Porphyromonas gingivalis Virulence

2019 ◽  
Vol 7 (12) ◽  
pp. 623
Author(s):  
Michał Śmiga ◽  
Teresa Olczak
Keyword(s):  
Oxidative Stress ◽  
Stress Response ◽  
Porphyromonas Gingivalis ◽  
Alternative Pathway ◽  
Redox Status ◽  
Oxidative Stress Response ◽  
Gene Encoding ◽  
Expression Of Genes ◽  
Genes Encoding ◽  
Redox Sensing

Porphyromonas gingivalis is one of the etiological agents of chronic periodontitis. Both heme and oxidative stress impact expression of genes responsible for its survival and virulence. Previously we showed that P. gingivalis ferric uptake regulator homolog affects expression of a gene encoding a putative Crp/Fnr superfamily member, termed P. gingivalis redox-sensing protein (PgRsp). Although PgRsp binds heme and shows the highest similarity to proteins assigned to the CooA family, it could be a member of a novel, separate family of proteins with unknown function. Expression of the pgrsp gene is autoregulated and iron/heme dependent. Genes encoding proteins engaged in the oxidative stress response were upregulated in the pgrsp mutant (TO11) strain compared with the wild-type strain. The TO11 strain showed higher biomass production, biofilm formation, and coaggregation ability with Tannerella forsythia and Prevotella intermedia. We suggest that PgRsp may regulate production of virulence factors, proteases, Hmu heme acquisition system, and FimA protein. Moreover, we observed growth retardation of the TO11 strain under oxidative conditions and decreased survival ability of the mutant cells inside macrophages. We conclude that PgRsp protein may play a role in the oxidative stress response using heme as a ligand for sensing changes in redox status, thus regulating the alternative pathway of the oxidative stress response alongside OxyR.

scholarly journals Release from Quorum-Sensing Molecules Triggers Hyphal Formation during Candida albicans Resumption of Growth

2005 ◽  
Vol 4 (7) ◽  
pp. 1203-1210 ◽  
Author(s):  
Brice Enjalbert ◽  
Malcolm Whiteway
Keyword(s):  
Candida Albicans ◽  
Quorum Sensing ◽  
Culture Medium ◽  
Pathogenic Fungus ◽  
Hyphal Growth ◽  
Growth Environment ◽  
Expression Of Genes ◽  
Genes Encoding ◽  
Hyphal Formation ◽  
Cyclin Genes

ABSTRACT Candida albicans is a pathogenic fungus able to change morphology in response to variations in its growth environment. Simple inoculation of stationary cells into fresh medium at 37°C, without any other manipulations, appears to be a powerful but transient inducer of hyphal formation; this process also plays a significant role in classical serum induction of hyphal formation. The mechanism appears to involve the release of hyphal repression caused by quorum-sensing molecules in the growth medium of stationary-phase cells, and farnesol has a strong but incomplete role in this process. We used DNA microarray technology to study both the resumption of growth of Candida albicans cells and molecular regulation involving farnesol. Maintaining farnesol in the culture medium during the resumption of growth both delays and reduces the induction of hypha-related genes yet triggers expression of genes encoding drug efflux components. The persistence of farnesol also prevents the repression of histone genes during hyphal growth and affects the expression of putative or demonstrated morphogenesis-regulating cyclin genes, such as HGC1, CLN3, and PCL2. The results suggest a model explaining the triggering of hyphae in the host based on quorum-sensing molecules.

scholarly journals Porphyromonas gingivalis Mfa1 Induces Chemokine and Cell Adhesion Molecules in Mouse Gingival Fibroblasts via Toll-Like Receptors

2020 ◽  
Vol 9 (12) ◽  
pp. 4004
Author(s):  
Yuhei Takayanagi ◽  
Takeshi Kikuchi ◽  
Yoshiaki Hasegawa ◽  
Yoshikazu Naiki ◽  
Hisashi Goto ◽  
...  
Keyword(s):  
Porphyromonas Gingivalis ◽  
Intercellular Adhesion Molecule ◽  
Gingival Fibroblasts ◽  
Toll Like Receptor ◽  
Tissue Destruction ◽  
Tlr2 Expression ◽  
Transfected Cells ◽  
Expression Of Genes ◽  
Genes Encoding

Porphyromonas gingivalis Mfa1 fimbriae are thought to act as adhesion factors and to direct periodontal tissue destruction but their immunomodulatory actions are poorly understood. Here, we investigated the effect of Mfa1 stimulation on the immune and metabolic mechanisms of gingival fibroblasts from periodontal connective tissue. We also determined the role of Toll-like receptor (TLR) 2 and TLR4 in Mfa1 recognition. Mfa1 increased the expression of genes encoding chemokine (C-X-C motif) ligand (CXCL) 1, CXCL3, intercellular adhesion molecule (ICAM) 1 and Selectin endothelium (E) in gingival fibroblasts, but did not have a significant effect on genes that regulate metabolism. Mfa1-stimulated up-regulation of genes was significantly suppressed in Tlr4 siRNA-transfected cells compared with that in control siRNA-transfected cells, which indicates that recognition by TLR4 is essential for immunomodulation by Mfa1. Additionally, suppression of Tlr2 expression partially attenuated the stimulatory effect of Mfa1. Overall, these results help explain the involvement of P. gingivalis Mfa1 fimbriae in the progression of periodontal disease.

scholarly journals LAMP2 Cardiomyopathy: Consequences of Impaired Autophagy in the Heart

2021 ◽  
Author(s):  
Ronny Alcalai ◽  
Michael Arad ◽  
Hiroko Wakimoto ◽  
Dor Yadin ◽  
Joshua Gorham ◽  
...  
Keyword(s):  
Cardiac Electrophysiology ◽  
Morphological Changes ◽  
Systolic Function ◽  
Left Ventricular ◽  
Danon Disease ◽  
Conduction Disturbances ◽  
Expression Of Genes ◽  
Genes Encoding ◽  
Increased Sensitivity ◽  
Protein Components

Background Human mutations in the X‐linked lysosome‐associated membrane protein‐2 ( LAMP2 ) gene can cause a multisystem Danon disease or a primary cardiomyopathy characterized by massive hypertrophy, conduction system abnormalities, and malignant ventricular arrhythmias. We introduced an in‐frame LAMP2 gene exon 6 deletion mutation (denoted L2 Δ6 ) causing human cardiomyopathy, into mouse LAMP2 gene, to elucidate its consequences on cardiomyocyte biology. This mutation results in in‐frame deletion of 41 amino acids, compatible with presence of some defective LAMP2 protein. Methods and Results Left ventricular tissues from L2 Δ6 and wild‐type mice had equivalent amounts of LAMP2 RNA, but a significantly lower level of LAMP2 protein. By 20 weeks of age male mutant mice developed left ventricular hypertrophy which was followed by left ventricular dilatation and reduced systolic function. Cardiac electrophysiology and isolated cardiomyocyte studies demonstrated ventricular arrhythmia, conduction disturbances, abnormal calcium transients and increased sensitivity to catecholamines. Myocardial fibrosis was strikingly increased in 40‐week‐old L2 Δ6 mice, recapitulating findings of human LAMP2 cardiomyopathy. Immunofluorescence and transmission electron microscopy identified mislocalization of lysosomes and accumulation of autophagosomes between sarcomeres, causing profound morphological changes disrupting the cellular ultrastructure. Transcription profile and protein expression analyses of L2 Δ6 hearts showed significantly increased expression of genes encoding activators and protein components of autophagy, hypertrophy, and apoptosis. Conclusions We suggest that impaired autophagy results in cardiac hypertrophy and profound transcriptional reactions that impacted metabolism, calcium homeostasis, and cell survival. These responses define the molecular pathways that underlie the pathology and aberrant electrophysiology in cardiomyopathy of Danon disease.

scholarly journals A Glucose Sensor in Candida albicans

2006 ◽  
Vol 5 (10) ◽  
pp. 1726-1737 ◽  
Author(s):  
Victoria Brown ◽  
Jessica A. Sexton ◽  
Mark Johnston
Keyword(s):  
Candida Albicans ◽  
Glucose Sensor ◽  
Glucose Sensing ◽  
Glucose Sensors ◽  
Glucose Levels ◽  
High Affinity ◽  
Expression Of Genes ◽  
Hexose Transporters ◽  
Genes Encoding ◽  
Sensor Glucose

ABSTRACT The Hgt4 protein of Candida albicans (orf19.5962) is orthologous to the Snf3 and Rgt2 glucose sensors of Saccharomyces cerevisiae that govern sugar acquisition by regulating the expression of genes encoding hexose transporters. We found that HGT4 is required for glucose induction of the expression of HGT12, HXT10, and HGT7, which encode apparent hexose transporters in C. albicans. An hgt4Δ mutant is defective for growth on fermentable sugars, which is consistent with the idea that Hgt4 is a sensor of glucose and similar sugars. Hgt4 appears to be sensitive to glucose levels similar to those in human serum (∼5 mM). HGT4 expression is repressed by high levels of glucose, which is consistent with the idea that it encodes a high-affinity sugar sensor. Glucose sensing through Hgt4 affects the yeast-to-hyphal morphological switch of C. albicans cells: hgt4Δ mutants are hypofilamented, and a constitutively signaling form of Hgt4 confers hyperfilamentation of cells. The hgt4Δ mutant is less virulent than wild-type cells in a mouse model of disseminated candidiasis. These results suggest that Hgt4 is a high-affinity glucose sensor that contributes to the virulence of C. albicans.

scholarly journals Genome-Wide Expression Profiling of the Response to Azole, Polyene, Echinocandin, and Pyrimidine Antifungal Agents in Candida albicans

2005 ◽  
Vol 49 (6) ◽  
pp. 2226-2236 ◽  
Author(s):  
Teresa T. Liu ◽  
Robin E. B. Lee ◽  
Katherine S. Barker ◽  
Richard E. Lee ◽  
Lai Wei ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Ergosterol Biosynthesis ◽  
Reverse Transcription Pcr ◽  
Expression Of Genes ◽  
Lipid Fatty Acid ◽  
Genes Encoding ◽  
Molecule Transport ◽  
Small Molecule Transport

ABSTRACT Antifungal agents exert their activity through a variety of mechanisms, some of which are poorly understood. We examined changes in the gene expression profile of Candida albicans following exposure to representatives of the four currently available classes of antifungal agents used in the treatment of systemic fungal infections. Ketoconazole exposure increased expression of genes involved in lipid, fatty acid, and sterol metabolism, including NCP1, MCR1, CYB5, ERG2, ERG3, ERG10, ERG25, ERG251, and that encoding the azole target, ERG11. Ketoconazole also increased expression of several genes associated with azole resistance, including CDR1, CDR2, IFD4, DDR48, and RTA3. Amphotericin B produced changes in the expression of genes involved in small-molecule transport (ENA21), and in cell stress (YHB1, CTA1, AOX1, and SOD2). Also observed was decreased expression of genes involved in ergosterol biosynthesis, including ERG3 and ERG11. Caspofungin produced changes in expression of genes encoding cell wall maintenance proteins, including the β-1,3-glucan synthase subunit GSL22, as well as PHR1, ECM21, ECM33, and FEN12. Flucytosine increased the expression of proteins involved in purine and pyrimidine biosynthesis, including YNK1, FUR1, and that encoding its target, CDC21. Real-time reverse transcription-PCR was used to confirm microarray results. Genes responding similarly to two or more drugs were also identified. These data shed new light on the effects of these classes of antifungal agents on C. albicans.

scholarly journals Community Development between Porphyromonas gingivalis and Candida albicans Mediated by InlJ and Als3

mBio ◽  
2018 ◽  
Vol 9 (2) ◽  
Author(s):  
Maryta N. Sztukowska ◽  
Lindsay C. Dutton ◽  
Christopher Delaney ◽  
Mark Ramsdale ◽  
Gordon Ramage ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Community Development ◽  
Periodontal Disease ◽  
Porphyromonas Gingivalis ◽  
Periodontal Diseases ◽  
Disease Process ◽  
Dependent Manner ◽  
Pathogenic Potential ◽  
Content Type ◽  
Polymicrobial Communities

ABSTRACT The pleiomorphic yeast Candida albicans is a significant pathogen in immunocompromised individuals. In the oral cavity, C. albicans is an inhabitant of polymicrobial communities, and interspecies interactions promote hyphal formation and biofilm formation. C. albicans colonizes the subgingival area, and the frequency of colonization increases in periodontal disease. In this study, we investigated the interactions between C. albicans and the periodontal pathogen Porphyromonas gingivalis . C. albicans and P. gingivalis were found to coadhere in both the planktonic and sessile phases. Loss of the internalin-family protein InlJ abrogated adhesion of P. gingivalis to C. albicans , and recombinant InlJ protein competitively inhibited interspecies binding. A mutant of C. albicans deficient in expression of major hyphal protein Als3 showed diminished binding to P. gingivalis , and InlJ interacted with Als3 heterologously expressed in Saccharomyces cerevisiae . Transcriptional profiling by RNA sequencing (RNA-Seq) established that 57 genes were uniquely upregulated in an InlJ-dependent manner in P. gingivalis - C. albicans communities, with overrepresentation of those corresponding to 31 gene ontology terms, including those associated with growth and division. Of potential relevance to the disease process, C. albicans induced upregulation of components of the type IX secretion apparatus. Collectively, these findings indicate that InlJ-Als3-dependent binding facilitates interdomain community development between C. albicans and P. gingivalis and that P. gingivalis has the potential for increased virulence within such communities. IMPORTANCE Many diseases involve the concerted actions of microorganisms assembled in polymicrobial communities. Inflammatory periodontal diseases are among the most common infections of humans and result in destruction of gum tissue and, ultimately, in loss of teeth. In periodontal disease, pathogenic communities can include the fungus Candida albicans ; however, the contribution of C. albicans to the synergistic virulence of the community is poorly understood. Here we characterize the interactions between C. albicans and the keystone bacterial pathogen Porphyromonas gingivalis and show that coadhesion mediated by specific proteins results in major changes in gene expression by P. gingivalis , which could serve to increase pathogenic potential. The work provides significant insights into interdomain interactions that can enhance our understanding of diseases involving a multiplicity of microbial pathogens.

scholarly journals The Transcription Factor Homolog CTF1 Regulates β-Oxidation in Candida albicans

2009 ◽  
Vol 8 (10) ◽  
pp. 1604-1614 ◽  
Author(s):  
Melissa A. Ramírez ◽  
Michael C. Lorenz
Keyword(s):  
Candida Albicans ◽  
Carbon Metabolism ◽  
Regulatory Network ◽  
Glyoxylate Cycle ◽  
Carbon Sources ◽  
Microbial Pathogens ◽  
Peroxisomal Biogenesis ◽  
Expression Of Genes ◽  
Genes Encoding ◽  
The Glyoxylate Cycle

ABSTRACT Carbon starvation is one of the many stresses to which microbial pathogens are subjected while in the host. Pathways necessary for the utilization of alternative carbon sources, such as gluconeogenesis, the glyoxylate cycle, and β-oxidation of fatty acids, have been shown to be required for full virulence in several systems, including the fungal pathogen Candida albicans. We have investigated the regulatory network governing alternative carbon metabolism in this organism through characterization of transcriptional regulators identified based on the model fungi, Saccharomyces cerevisiae and Aspergillus nidulans. C. albicans has homologs of the ScCAT8/AnFacB and ScADR1/AnAmdX transcription factors that regulate induction of genes encoding the proteins of gluconeogenesis, the glyoxylate cycle, and ethanol utilization. Surprisingly, C. albicans mutants lacking CAT8 or ADR1 have no apparent phenotypes and do not regulate genes for key enzymes of these pathways. Fatty acid degradation and peroxisomal biogenesis are controlled by nonhomologous regulators, OAF1/PIP2 in S. cerevisiae and FarA/FarB in A. nidulans; C. albicans is missing OAF1 and PIP2 and, instead, has a single homolog of the Far proteins, CTF1. We have shown that CTF1 is required for growth on lipids and for expression of genes necessary for β-oxidation, such as FOX2. ctf1Δ/ctf1Δ (ctf1Δ/Δ) strains do not, however, show the pleiotropic phenotypes observed for fox2Δ/Δ mutants. The ctf1Δ/Δ mutant confers a mild attenuation in virulence, like the fox2Δ/Δ mutant. Thus, phenotypic and genotypic observations highlight important differences in the regulatory network for alternative carbon metabolism in C. albicans compared to the paradigms developed in other model fungi.

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