scholarly journals Bmh1p (14-3-3) mediates pathways associated with virulence in Candida albicans

Microbiology ◽  
2009 ◽  
Vol 155 (5) ◽  
pp. 1536-1546 ◽  
Author(s):  
Michelle N. Kelly ◽  
Douglas A. Johnston ◽  
Bethany A. Peel ◽  
Timothy W. Morgan ◽  
Glen E. Palmer ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Mouse Model ◽  
Virulence Factors ◽  
Environmental Changes ◽  
Pathogenic Fungus ◽  
Binding Pocket ◽  
Lag Phase ◽  
Models Of Disease

The ability of the pathogenic fungus Candida albicans to cause disease requires rapid adaptation to changes in the host environment and to an evolving host immune response. The identification of ‘virulence factors’ using in vitro characterization of mutant strains has traditionally relied on a common set of phenotypic and biochemical assays (most often performed at 30 °C) and the subsequent correlation with their corresponding virulence in mouse models of disease. Utilizing a panel of isogenic mutants for the multifunctional signal-modulating 14-3-3 protein (Bmh1p), we have found that specific mutations affect a variety of different pathways currently associated with virulence, including those involved with the formation of filaments, as well as interaction with host immune cells. Surprisingly, our studies revealed that deficiencies in many of these pathways do not always correlate with virulence in a mouse model of disseminated infection. Mutations within the binding pocket of Bmh1p that affect the ability of the protein to efficiently bind ligand had varying effects on the results of a number of in vitro and in vivo assays. The capability, in vitro, to filament in embedment conditions, and to filament and form chlamydospores under microaerophilic conditions on cornmeal agar, does not correlate with virulence. It is likely that only a subset of hyphal signalling pathways is actually required for the establishment of infection in the disseminated mouse model. Most importantly, our results suggest that the delayed onset of lag-phase growth in vitro at 37 °C, and not at 30 °C, results in an inability of these mutants to rapidly adjust to environmental changes in vivo and may be responsible for their increased clearance and reduced virulence. It is critical, therefore, that future in vitro studies of putative virulence factors in C. albicans include careful characterization at physiological temperatures.

scholarly journals Antimicrobial Photodynamic Inactivation Inhibits Candida albicans Virulence Factors and ReducesIn VivoPathogenicity

2012 ◽  
Vol 57 (1) ◽  
pp. 445-451 ◽  
Author(s):  
Ilka Tiemy Kato ◽  
Renato Araujo Prates ◽  
Caetano Padial Sabino ◽  
Beth Burgwyn Fuchs ◽  
George P. Tegos ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Virulence Factors ◽  
Sodium Dodecyl ◽  
Systemic Infection ◽  
Tube Formation ◽  
Photodynamic Inactivation ◽  
Content Type ◽  
Daughter Cells

ABSTRACTThe objective of this study was to evaluate whetherCandida albicansexhibits altered pathogenicity characteristics following sublethal antimicrobial photodynamic inactivation (APDI) and if such alterations are maintained in the daughter cells.C. albicanswas exposed to sublethal APDI by using methylene blue (MB) as a photosensitizer (0.05 mM) combined with a GaAlAs diode laser (λ 660 nm, 75 mW/cm2, 9 to 27 J/cm2).In vitro, we evaluated APDI effects onC. albicansgrowth, germ tube formation, sensitivity to oxidative and osmotic stress, cell wall integrity, and fluconazole susceptibility.In vivo, we evaluatedC. albicanspathogenicity with a mouse model of systemic infection. Animal survival was evaluated daily. Sublethal MB-mediated APDI reduced the growth rate and the ability ofC. albicansto form germ tubes compared to untreated cells (P< 0.05). Survival of mice systemically infected withC. albicanspretreated with APDI was significantly increased compared to mice infected with untreated yeast (P< 0.05). APDI increasedC. albicanssensitivity to sodium dodecyl sulfate, caffeine, and hydrogen peroxide. The MIC for fluconazole forC. albicanswas also reduced following sublethal MB-mediated APDI. However, none of those pathogenic parameters was altered in daughter cells ofC. albicanssubmitted to APDI. These data suggest that APDI may inhibit virulence factors and reducein vivopathogenicity ofC. albicans. The absence of alterations in daughter cells indicates that APDI effects are transitory. The MIC reduction for fluconazole following APDI suggests that this antifungal could be combined with APDI to treatC. albicansinfections.

scholarly journals Identification of the Putative Protein Phosphatase Gene PTC1 as a Virulence-Related Gene Using a Silkworm Model of Candida albicans Infection

2008 ◽  
Vol 7 (10) ◽  
pp. 1640-1648 ◽  
Author(s):  
Nozomu Hanaoka ◽  
Yukie Takano ◽  
Kazutoshi Shibuya ◽  
Hajime Fugo ◽  
Yoshimasa Uehara ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Mouse Model ◽  
Protein Phosphatase ◽  
Protein Phosphatases ◽  
Hyphal Growth ◽  
Marker Genes ◽  
Phenotypic Traits ◽  
Putative Protein

ABSTRACT Protein phosphatases are critical for the regulation of many cellular processes. Null mutants of 21 putative protein phosphatases of Candida albicans were constructed by consecutive allele replacement using the URA3 and ARG4 marker genes. A simple silkworm model of C. albicans infection was used to screen the panel of mutants. Four null mutant (cmp1Δ, yvh1Δ, sit4Δ, and ptc1Δ) strains showed attenuated virulence in the silkworm model relative to that of control and parental strains. Three of the mutants, the cmp1Δ, yvh1Δ, and sit4Δ mutants, had previously been identified as affecting virulence in a conventional mouse model, indicating the validity of the silkworm model screen. Disruption of the putative protein phosphatase gene PTC1 of C. albicans, which has 52% identity to the Saccharomyces cerevisiae type 2C protein phosphatase PTC1, significantly reduced virulence in the silkworm model. The mutant was also avirulent in a mouse model of disseminated candidiasis. Reintroducing either of the C. albicans PTC1 alleles into the disruptant strain, using a cassette containing either allele under the control of a constitutive ACT1 promoter, restored virulence in both infection models. Characterization of ptc1Δ revealed other phenotypic traits, including reduced hyphal growth in vitro and in vivo, and reduced extracellular proteolytic activity. We conclude that PTC1 may contribute to pathogenicity in C. albicans.

scholarly journals Application of Hydro-ethanol Extract of Tithonia diversifolia (Hemsl) in the Treatment of Experimental Murine Oral Candidiasis

2019 ◽  
pp. 1-10
Author(s):  
Oluwole Moses David ◽  
Margaret Olutayo Alese ◽  
Tobi Oyewole ◽  
Oluwole Ojo Alese ◽  
Adekunle Adegbuyi ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Virulence Factors ◽  
Oral Candidiasis ◽  
Ethanolic Extract ◽  
Alcoholic Extract ◽  
Tithonia Diversifolia ◽  
Candida Spp ◽  
Oral Infections

Background: Oral infection caused by Candida spp. is a major healthcare problem in dental and oral care. Treatment failure has been reported in cases of oral candidiasis as a result of resistance to common antifungals. Aim and Objective: In this study, the in vitro and in vivo activities of extract of Tithonia diversifolia against virulence factor-borne and antifungal resistant-Candida albicans were investigated. Candida albicans was isolated from the saliva of patients attending a tertiary hospital in Ekiti State. Methodology: Standard methods were used to determine the presence of virulence factors in the isolates. In vitro and in vivo anti-candidal activities of the hydro-ethanolic extract of T. diversifolia were also tested on the test fungus. Results: The virulence factors have varying percentage of occurrence in all the isolates with catalase having the highest. Itraconazole and nystatin were not effective against the isolates. Out of the six isolates selected (based on antifungal resistance) only three produced strong biofilm. The reduction in the population of the test organisms by the extract was time and concentration dependent. At the end of candidal challenge and treatment assays, extract of T. diversifolia has lower anti-candidal property compared to nystatin. Conclusion: This study has shown that C. albicans associated with the mouth carries virulence factors and are resistant to common antifungals. In this work, we noticed antifungal effects of hydro-alcoholic extract of T. diversifolia on C. albicans associated with oral infections.

scholarly journals Effect of Farnesol on a Mouse Model of Systemic Candidiasis, Determined by Use of a DPP3 Knockout Mutant of Candida albicans

2007 ◽  
Vol 75 (4) ◽  
pp. 1609-1618 ◽  
Author(s):  
Dhammika H. M. L. P. Navarathna ◽  
Jacob M. Hornby ◽  
Navasona Krishnan ◽  
Anne Parkhurst ◽  
Gerald E. Duhamel ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Mouse Model ◽  
Tween 80 ◽  
Sublethal Dose ◽  
Systemic Candidiasis ◽  
Knockout Mutant ◽  
Gene Encoding

ABSTRACTThis work extends our previous observation that the fungusCandida albicanssecretes micromolar levels of farnesol and that accumulation of farnesol in vitro prevents the yeast-to-mycelium conversion in a quorum-sensing manner. What does farnesol do in vivo? The purpose of this study was to determine the role of farnesol during infection with a well-established mouse model of systemic candidiasis withC. albicansA72 administered by tail vein injection. This question was addressed by altering both endogenous and exogenous farnesol. For endogenous farnesol, we created a knockout mutation inDPP3, the gene encoding a phosphatase which converts farnesyl pyrophosphate to farnesol. This mutant (KWN2) produced six times less farnesol and was ca. 4.2 times less pathogenic than its SN152 parent. The strain withDPP3reconstituted (KWN4) regained both its farnesol production levels and pathogenicity. These mutants (KWN1 to KWN4) retained their full dimorphic capability. With regard to exogenous farnesol, farnesol was administered either intraperitoneally (i.p.) or orally in the drinking water. Mice receivingC. albicansintravenously and farnesol (20 mM) orally had enhanced mortality (P< 0.03). Similarly, mice (n= 40) injected with 1.0 ml of 20 mM farnesol i.p. had enhanced mortality (P< 0.03), and the onset of mortality was 30 h sooner than for mice which received a control injection without farnesol. The effect of i.p. farnesol was more pronounced (P< 0.04) when mice were inoculated with a sublethal dose ofC. albicans. These mice started to die 4 days earlier, and the percent survival on day 6 postinoculation (p.i.) was five times lower than for mice receivingC. albicanswith control i.p. injections. In all experiments, mice administered farnesol alone or Tween 80 alone remained normal throughout a 14-day observation period. Finally, beginning at 12 h p.i., higher numbers ofC. albicanscells were detected in kidneys from mice receiving i.p. farnesol than in those from mice receiving control i.p. injections. Thus, reduced endogenous farnesol decreased virulence, while providing exogenous farnesol increased virulence. Taken together, these data suggest that farnesol may play a role in disease pathogenesis, either directly or indirectly, and thus may represent a newly identified virulence factor.

scholarly journals Tetracycline-Regulatable System To Tightly Control Gene Expression in the Pathogenic Fungus Candida albicans

2000 ◽  
Vol 68 (12) ◽  
pp. 6712-6719 ◽  
Author(s):  
Hironobu Nakayama ◽  
Toshiyuki Mio ◽  
Shigehisa Nagahashi ◽  
Michiko Kokado ◽  
Mikio Arisawa ◽  
...  
Keyword(s):  
Gene Expression ◽  
Candida Albicans ◽  
Culture Media ◽  
Pathogenic Fungus ◽  
Elongation Factor ◽  
Growth Defect ◽  
Control Gene ◽  
Control Gene Expression

ABSTRACT Conventional tools for elucidating gene function are relatively scarce in Candida albicans, the most prevalent human fungal pathogen. To this end, we developed a convenient system to control gene expression in C. albicans by the tetracycline-regulatable (TR) promoters. When the sea pansy Renilla reniformisluciferase gene (RLUC1) was placed under the control of this system, doxycycline (DOX) inhibited the luciferase activity almost completely. In the absence of DOX, the RLUC1 gene was induced to express luciferase at a level 400- to 1,000-fold higher than that in the presence of DOX. The same results were obtained in hypha-forming cells. The replacement ofN-myristoyltransferase or translation elongation factor 3 promoters with TR promoters conferred a DOX-dependent growth defect in culture media. Furthermore, all the mice infected with these mutants, which are still virulent, survived following DOX administration. Consistently, we observed that the number of these mutant cells recovered from the mouse kidneys was significantly reduced following DOX administration. Thus, this system is useful for investigating gene functions, since this system is able to function in both in vitro and in vivo settings.

scholarly journals An Azole-Tolerant Endosomal Trafficking Mutant of Candida albicans Is Susceptible to Azole Treatment in a Mouse Model of Vaginal Candidiasis

2017 ◽  
Vol 61 (6) ◽  
Author(s):  
Brian M. Peters ◽  
Arturo Luna-Tapia ◽  
Hélène Tournu ◽  
Jeffrey M. Rybak ◽  
P. David Rogers ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Mouse Model ◽  
Vaginal Candidiasis ◽  
Azole Resistance ◽  
Endosomal Trafficking ◽  
Wild Type ◽  
Content Type ◽  
Azole Antifungals

ABSTRACT We recently reported that a Candida albicans endosomal trafficking mutant continues to grow after treatment with the azole antifungals. Herein, we report that the vps21Δ/Δ mutant does not have a survival advantage over wild-type isolates after fluconazole treatment in a mouse model of vaginal candidiasis. Furthermore, loss of VPS21 does not synergize with established mechanisms of azole resistance, such as overexpression of efflux pumps or of Erg11p, the target enzyme of the azoles. In summary, although loss of VPS21 function enhances C. albicans survival after azole treatment in vitro, it does not seem to affect azole susceptibility in vivo.

VI.Entamoeba histolytica: parasite-host interactions

2001 ◽  
Vol 280 (6) ◽  
pp. G1049-G1054 ◽  
Author(s):  
Samuel L. Stanley ◽  
Sharon L. Reed
Keyword(s):  
Virulence Factors ◽  
Host Response ◽  
Host Cells ◽  
Intestinal Epithelial ◽  
Small Peptides ◽  
In Vivo Models ◽  
Host Interactions ◽  
Models Of Disease

The protozoan intestinal parasite Entamoeba histolytica remains a significant cause of morbidity and mortality worldwide. E. histolytica causes two major clinical syndromes, amebic colitis and amebic liver abscess. Recent advances in the development of in vitro and in vivo models of disease, new genetic approaches, the identification of key E. histolytica virulence factors, and the recognition of crucial elements of the host response to infection have led to significant insights into the pathogenesis of amebic infection. E. histolytica virulence factors include 1) a surface galactose binding lectin that mediates E. histolyticabinding to host cells and may contribute to amebic resistance to complement, 2) amebapores, small peptides capable of lysing cells, which may play a role in killing intestinal epithelial cells, hepatocytes, and host defense cells, and 3) a family of secreted cysteine proteinases that play a key role in E. histolytica tissue invasion, evasion of host defenses, and parasite induction of gut inflammation. Amebae can both lyse host cells and induce their suicide through programmed cell death. The host response is also an important factor in the outcome of infection, and neutrophils may play a key role in contributing to the tissue damage seen in amebiasis and in controlling amebic infection.

scholarly journals Global Transcriptomic Analysis of the Candida albicans Response to Treatment with a Novel Inhibitor of Filamentation

mSphere ◽  
2019 ◽  
Vol 4 (5) ◽  
Author(s):  
Jesus A. Romo ◽  
Hao Zhang ◽  
Hong Cai ◽  
David Kadosh ◽  
Julia R. Koehler ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Small Molecule ◽  
Pathogenic Fungus ◽  
Transcriptional Profiling ◽  
Response To Treatment ◽  
Sequencing Analysis ◽  
Transport Pathways ◽  
Content Type

ABSTRACT The opportunistic pathogenic fungus Candida albicans can cause devastating infections in immunocompromised patients. Its ability to undergo a morphogenetic transition from yeast to filamentous forms allows it to penetrate tissues and damage tissues, and the expression of genes associated with a number of pathogenetic mechanisms is also coordinately regulated with the yeast-to-hypha conversion. Therefore, it is widely considered that filamentation represents one of the main virulence factors of C. albicans. We have previously identified N-[3-(allyloxy)-phenyl]-4-methoxybenzamide (compound 9029936) as the lead compound in a series of small-molecule inhibitors of C. albicans filamentation and characterized its activity both in vitro and in vivo. This compound appears to be a promising candidate for the development of alternative antivirulence strategies for the treatment of C. albicans infections. In this study, we performed RNA sequencing analysis of samples obtained from C. albicans cells grown under filament-inducing conditions in the presence or absence of this compound. Overall, treatment with compound 9029936 resulted in 618 upregulated and 702 downregulated genes. Not surprisingly, some of the most downregulated genes included well-characterized genes associated with filamentation and virulence such as SAP5, ECE1 (candidalysin), and ALS3, as well as genes that impact metal chelation and utilization. Gene ontology analysis revealed an overrepresentation of cell adhesion, iron transport, filamentation, biofilm formation, and pathogenesis processes among the genes downregulated during treatment with this leading compound. Interestingly, the top upregulated genes suggested an enhancement of vesicular transport pathways, particularly those involving SNARE interactions. IMPORTANCE These results from whole-genome transcriptional profiling provide further insights into the biological activity and mode of action of a small-molecule inhibitor of C. albicans filamentation. This information will assist in the development of novel antivirulence strategies against C. albicans infections.

scholarly journals In vivo and in vitro Pathogenesis and Virulence Factors of Candida albicans Strains Isolated from Cutaneous Candidiasis

2020 ◽  
Vol 24 (5) ◽  
pp. 319-327
Author(s):  
Golnar Sadeghi ◽  
Seyed Fazllolah Mousavi ◽  
Mina Ebrahimi-Rad ◽  
Esmat Mirabzadeh-Ardekani ◽  
Ali Eslamifar ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Virulence Factors ◽  
Cutaneous Candidiasis
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