How Flies Find Fungal Foes

2007 ◽  
Vol 2007 (369) ◽  
pp. tw21-tw21
Author(s):  
L. Bryan Ray
Keyword(s):  
Cell Wall ◽  
Virulence Factors ◽  
Defense Mechanism ◽  
Fungal Infections ◽  
Toll Pathway ◽  
Online Journal ◽  
Gene Encoding ◽  
Fungal Virulence

Responses of the immune systems of plants and animals show what appears to be evidence of ancient attacks and counterattacks by pathogens and their hosts in the battle for survival. Drosophila have developed receptors that recognize constituents of bacterial cell walls and mount an immune response that causes proteolytic cleavage of the cytokine Spätzle. The Spätzle fragment then activates Toll receptors and leads to production of antimicrobial peptides. Gottar et al. explored the response of Drosophila to fungal infections and found a similar defense mechanism but also unveiled a second signaling pathway that detects a virulence factor produced by the fungus. The authors infected flies by pricking them with a needle dipped in fungus-containing solution and monitored survival or Toll-dependent expression of the gene encoding an antifungal peptide. They found that the receptor GNBP3 (Gram-negative binding protein 3) was required for detection of cell wall components of the fungi and consequent activation of Toll receptors. However, cells with a mutated GNB3 protein could still respond to fungi and activate Toll, but in this case cell wall-derived components were not the trigger. This response depended on the presence of live fungi and, presumably, the production of virulence factors. One such factor is the protease PR1, and the authors showed that expression of PR1 alone led to activation of the Toll pathway. Knowing that a fly protease PSH (Persephone), which is thought to participate in a cascade of proteases that lead to Spätzle cleavage and activation of the Toll pathway in response to fungi, itself requires proteolytic removal of a prodomain for activity, the authors tested whether PR1 might activate PSH. Indeed, studies in vitro and in vivo indicated that PSH appears to be a direct substrate of PR1. The fungi use the PR1 protease to break down the protective cuticle of the insect and allow infection. The authors propose that PSH acts like a sensor to monitor the status of the cuticle. If the presence of PR1 shows that the defense barrier is being broken, PSH is cleaved and the antimicrobial signaling is initiated. Whether humans have such a sensor system to recognize fungal virulence factors remains unknown.M. Gottar, V. Gobert, A. A. Matskevich, J.-M. Reichhart, C. Wang, T. M. Butt, M. Belvin, J. A. Hoffmann, D. Ferrandon, Dual detection of fungal infections in Drosophila via recognition of glucans and sensing of virulence factors. Cell127, 1425-1437 (2006). [Online Journal]

scholarly journals Antigen 84, an Effector of Pleiomorphism in Mycobacterium smegmatis

2007 ◽  
Vol 189 (21) ◽  
pp. 7896-7910 ◽  
Author(s):  
Liem Nguyen ◽  
Nicole Scherr ◽  
John Gatfield ◽  
Anne Walburger ◽  
Jean Pieters ◽  
...  
Keyword(s):  
Cell Wall ◽  
Mycobacterium Smegmatis ◽  
Cell Shape ◽  
Gene Disruption ◽  
Gene Encoding ◽  
Peptidoglycan Biosynthesis ◽  
Asymmetrically Distributed ◽  
Cell Wall Expansion

ABSTRACT While in most rod-shaped bacteria, morphology is based on MreB-like proteins that form an actin-like cytoskeletal scaffold for cell wall biosynthesis, the factors that determine the more flexible rod-like shape in actinobacteria such as Mycobacterium species are unknown. Here we show that a Mycobacterium smegmatis protein homologous to eubacterial DivIVA-like proteins, including M. tuberculosis antigen 84 (Ag84), localized symmetrically to centers of peptidoglycan biosynthesis at the poles and septa. Controlled gene disruption experiments indicated that the gene encoding Ag84, wag31, was essential; when overexpressed, cells became longer and wider, with Ag84 asymmetrically distributed at one pole. Many became grossly enlarged, bowling-pin-shaped cells having up to 80-fold-increased volume. In these cells, Ag84 accumulated predominantly at a bulbous pole that was apparently generated by uncontrolled cell wall expansion. In some cells, Ag84 was associated with exceptional sites of cell wall expansion (buds) that evolved into branches. M. bovis BCG Ag84 was able to form oligomers in vitro, perhaps reflecting its superstructure in vivo. These data suggested a role for Ag84 in cell division and modulating cell shape in pleiomorphic actinobacteria.

The fungal-specific subunit i/j of F1FO-ATP synthase stimulates the pathogenicity of Candida albicans independent of oxidative phosphorylation

2020 ◽  
Author(s):  
Yajing Zhao ◽  
Yan Lyu ◽  
Yanli Zhang ◽  
Shuixiu Li ◽  
Yishan Zhang ◽  
...  
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
Oxidative Phosphorylation ◽  
Atp Synthase ◽  
Fungal Infections ◽  
Critical Role ◽  
Antifungal Drug ◽  
F1fo Atp Synthase

Abstract Invasive fungal infections are a major cause of human mortality due in part to a very limited antifungal drug arsenal. The identification of fungal-specific pathogenic mechanisms is considered a crucial step to current antifungal drug development and represents a significant goal to increase the efficacy and reduce host toxicity. Although the overall architecture of F1FO-ATP synthase is largely conserved in both fungi and mammals, the subunit i/j (Su i/j, Atp18) and subunit k (Su k, Atp19) are proteins not found in mammals and specific to fungi. Here, the role of Su i/j and Su k in Candida albicans was characterized by an in vivo assessment of the virulence and in vitro growth and mitochondrial function. Strikingly, the atp18Δ/Δ mutant showed significantly reduced pathogenicity in systemic murine model. However, this substantial defect in infectivity exists without associated defects in mitochondrial oxidative phosphorylation or proliferation in vitro. Analysis of virulence-related traits reveals normal in both mutants, but shows cell wall defects in composition and architecture in the case of atp18Δ/Δ. We also find that the atp18Δ/Δ mutant is more susceptible to attack by macrophages than wild type, which may correlate well with the abnormal cell wall function and increased sensitivity to oxidative stress. In contrast, no significant changes were observed in any of these studies for the atp19Δ/Δ. These results demonstrate that the fungal-specific Su i/j, but not Su k of F1FO-ATP synthase may play a critical role in C. albicans infectivity and represent another opportunity for new therapeutic target investigation. Lay Abstract This study aims to investigate biological functions of fungal-specific subunit i/j and subunit k of ATP synthase in C. albicans oxidative phosphorylation and virulence potential. Our results revealed that subunit i/j, and not subunit k, is critical for C. albicans pathogenicity.

scholarly journals Comparative Analysis of the Capacity of the Candida Species To Elicit Vaginal Immunopathology

2018 ◽  
Vol 86 (12) ◽  
Author(s):  
Hubertine M. E. Willems ◽  
David J. Lowes ◽  
Katherine S. Barker ◽  
Glen E. Palmer ◽  
Brian M. Peters
Keyword(s):  
Comparative Analysis ◽  
Mucosal Damage ◽  
Neutrophil Recruitment ◽  
Cytokine Signaling ◽  
Vaginal Mucosa ◽  
Gene Encoding ◽  
Fungal Virulence ◽  
Content Type

ABSTRACT The human fungal pathogen Candida albicans is the major etiological agent of vulvovaginal candidiasis (VVC). Despite this fact, other non-albicans Candida (NAC) species have frequently been reported, as well. Despite their presence in the vaginal environment, little is known about their capacities to elicit immune responses classically associated with C. albicans-mediated immunopathology, including neutrophil recruitment and proinflammatory cytokine signaling. Therefore, using a combination of in vitro and in vivo approaches, we undertook a comparative analysis to determine whether a representative panel of NAC species could colonize, induce immunopathological markers, or cause damage at the vaginal mucosa. Using a murine model of VVC, C. albicans was found to induce robust immunopathology (neutrophils and interleukin 1β [IL-1β]) and elicit mucosal damage. However, all the NAC species tested (including C. dubliniensis, C. tropicalis, C. parapsilosis, C. krusei, C. glabrata, and C. auris) induced significantly less damage and neutrophil recruitment than C. albicans, despite achieving similar early colonization levels. These results largely correlated with a notable lack of ability by the NAC species (including C. dubliniensis and C. tropicalis) to form hyphae both in vitro and in vivo. Furthermore, both C. dubliniensis and C. tropicalis induced significantly less expression of the ECE1 gene encoding candidalysin, a key fungal virulence determinant driving VVC immunopathology. In order to determine the relative capacities of these species to elicit inflammasome-dependent IL-1β release, both wild-type and NLRP3−/− THP-1 cells were challenged in vitro. While most species tested elicited only modest amounts of IL-1β, challenge with C. albicans led to significantly elevated levels that were largely NLRP3 dependent. Collectively, our findings demonstrate that although NAC species are increasingly reported as causative agents of VVC, C. albicans appears to be exceedingly vaginopathogenic, exhibiting robust immunopathology, hypha formation, and candidalysin expression. Thus, this study provides mechanistic insight into why C. albicans is overwhelmingly the major pathogen reported during VVC.

scholarly journals Nuclear export of misfolded SOD1 mediated by a normally buried NES-like sequence reduces proteotoxicity in the nucleus

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Yongwang Zhong ◽  
Jiou Wang ◽  
Mark J Henderson ◽  
Peixin Yang ◽  
Brian M Hagen ◽  
...  
Keyword(s):  
Nuclear Export ◽  
Defense Mechanism ◽  
Consensus Sequence ◽  
Nuclear Export Signal ◽  
Egg Laying ◽  
Gene Encoding ◽  
Mutant Sod1 ◽  
Misfolded Sod1

Over 170 different mutations in the gene encoding SOD1 all cause amyotrophic lateral sclerosis (ALS). Available studies have been primarily focused on the mechanisms underlying mutant SOD1 cytotoxicity. How cells defend against the cytotoxicity remains largely unknown. Here, we show that misfolding of ALS-linked SOD1 mutants and wild-type (wt) SOD1 exposes a normally buried nuclear export signal (NES)-like sequence. The nuclear export carrier protein CRM1 recognizes this NES-like sequence and exports misfolded SOD1 to the cytoplasm. Antibodies against the NES-like sequence recognize misfolded SOD1, but not native wt SOD1 both in vitro and in vivo. Disruption of the NES consensus sequence relocalizes mutant SOD1 to the nucleus, resulting in higher toxicity in cells, and severer impairments in locomotion, egg-laying, and survival in Caenorhabditis elegans. Our data suggest that SOD1 mutants are removed from the nucleus by CRM1 as a defense mechanism against proteotoxicity of misfolded SOD1 in the nucleus.

scholarly journals Uridine Diphosphate–Glucose Transport into the Endoplasmic Reticulum ofSaccharomyces cerevisiae:In Vivo and In Vitro Evidence

1999 ◽  
Vol 10 (4) ◽  
pp. 1019-1030 ◽  
Author(s):  
Olga Castro ◽  
Ling Yun Chen ◽  
Armando J. Parodi ◽  
Claudia Abeijón
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Wall ◽  
Glucose Transport ◽  
Subcellular Location ◽  
Functional Expression ◽  
Uridine Diphosphate ◽  
Gene Encoding ◽  
Sugar Nucleotide

It has been proposed that synthesis of β-1,6-glucan, one ofSaccharomyces cerevisiae cell wall components, is initiated by a uridine diphosphate (UDP)-glucose–dependent reaction in the lumen of the endoplasmic reticulum (ER). Because this sugar nucleotide is not synthesized in the lumen of the ER, we have examined whether or not UDP–glucose can be transported across the ER membrane. We have detected transport of this sugar nucleotide into the ER in vivo and into ER–containing microsomes in vitro. Experiments with ER-containing microsomes showed that transport of UDP–glucose was temperature dependent and saturable with an apparentKmof 46 μM and a Vmaxof 200 pmol/mg protein/3 min. Transport was substrate specific because UDP–N-acetylglucosamine did not enter these vesicles. Demonstration of UDP–glucose transport into the ER lumen in vivo was accomplished by functional expression of Schizosaccharomyces pombe UDP–glucose:glycoprotein glucosyltransferase (GT) inS. cerevisiae, which is devoid of this activity. Monoglucosylated protein-linked oligosaccharides were detected inalg6 or alg5 mutant cells, which transfer Man9GlcNAc2to protein; glucosylation was dependent on the inhibition of glucosidase II or the disruption of the gene encoding this enzyme. Although S. cerevisiae lacks GT, it contains Kre5p, a protein with significant homology and the same size and subcellular location as GT. Deletion mutants, kre5Δ, lack cell wall β-1,6 glucan and grow very slowly. Expression of S. pombe GT in kre5Δ mutants did not complement the slow-growth phenotype, indicating that both proteins have different functions in spite of their similarities.

scholarly journals Inhibition of classical and alternative modes of respiration in C. albicans leads to cell wall remodelling and increased macrophage recognition

2018 ◽  
Author(s):  
Lucian Duvenage ◽  
Louise A. Walker ◽  
Aleksandra Bojarczuk ◽  
Simon A. Johnston ◽  
Donna M. MacCallum ◽  
...  
Keyword(s):  
Cell Wall ◽  
Electron Transport ◽  
Fungal Pathogen ◽  
Fungal Infections ◽  
Oxidase Inhibitor ◽  
Nitric Oxide Donor ◽  
Mammalian Host ◽  
Human Fungal Pathogen

AbstractThe human fungal pathogen C. albicans requires respiratory function for normal growth, morphogenesis and virulence. As such the mitochondria represent an enticing target for the development of new antifungal strategies. This possibility is further bolstered by the presence of fungal specific characteristics. However, respiration in C. albicans, as is the case in many fungal organisms, is facilitated by redundant electron transport mechanisms that makes direct inhibition a challenge. In addition, many chemicals known to target the electron transport chain are highly toxic. Here we make use of chemicals with low toxicity in mammals to efficiently inhibit respiration in C. albicans. We find that use of the Nitric Oxide donor, Sodium Nitroprusside (SNP), and the alternative oxidase inhibitor, SHAM, prevent respiration, lead to a loss in viability and to cell wall rearrangements that increase the rate of uptake by macrophages in vitro and in vivo. We propose that SNP+SHAM treatment leads to transcriptional changes that drive cell wall re-arrangement but which also prime cells to activate transition to hyphal growth. In line with this we find that pre-treatment of C. albicans with SNP+SHAM leads to an increase in virulence. Our data reveals strong links between respiration, cell wall remodelling and activation of virulence factors. Our findings also demonstrate that respiration in C. albicans can be efficiently inhibited with chemicals which are not damaging to the mammalian host, but that we need to develop a deeper understanding of the roles of mitochondria in cellular signalling if they are to be developed successfully as a target for new antifungals.Author SummaryCurrent approaches to tackling fungal infections are limited and new targets must be identified to protect against the emergence of resistant strains. We investigate the potential of targeting mitochondria, organelles required for energy production, growth and virulence, in the yeast human fungal pathogen Candida albicans. Our findings suggest that mitochondria can be targeted using drugs that can be tolerated by humans and that this treatment enhances their recognition by immune cells. However release of C. albicans cells from mitochondrial inhibition appears to activate a stress response that increases traits associated with virulence. Our results make it clear that mitochondria are a valid target for the development of anti-fungal strategies but that we must determine the mechanisms by which they regulate stress signalling and virulence ahead of successful therapeutic advance.

scholarly journals Critical Assessment of Cell Wall Integrity Factors Contributing to in vivo Echinocandin Tolerance and Resistance in Candida glabrata

2021 ◽  
Vol 12 ◽  
Author(s):  
Rocio Garcia-Rubio ◽  
Rosa Y. Hernandez ◽  
Alissa Clear ◽  
Kelley R. Healey ◽  
Erika Shor ◽  
...  
Keyword(s):  
Cell Wall ◽  
Candida Glabrata ◽  
Fungal Infections ◽  
Critical Role ◽  
Cell Wall Integrity ◽  
Fungal Cell ◽  
Fungal Host

Fungal infections are on the rise, and emergence of drug-resistant Candida strains refractory to treatment is particularly alarming. Resistance to azole class antifungals, which have been extensively used worldwide for several decades, is so high in several prevalent fungal pathogens, that another drug class, the echinocandins, is now recommended as a first line antifungal treatment. However, resistance to echinocandins is also prominent, particularly in certain species, such as Candida glabrata. The echinocandins target 1,3-β-glucan synthase (GS), the enzyme responsible for producing 1,3-β-glucans, a major component of the fungal cell wall. Although echinocandins are considered fungicidal, C. glabrata exhibits echinocandin tolerance both in vitro and in vivo, where a subset of the cells survives and facilitates the emergence of echinocandin-resistant mutants, which are responsible for clinical failure. Despite this critical role of echinocandin tolerance, its mechanisms are still not well understood. Additionally, most studies of tolerance are conducted in vitro and are thus not able to recapitulate the fungal-host interaction. In this study, we focused on the role of cell wall integrity factors in echinocandin tolerance in C. glabrata. We identified three genes involved in the maintenance of cell wall integrity – YPS1, YPK2, and SLT2 – that promote echinocandin tolerance both in vitro and in a mouse model of gastrointestinal (GI) colonization. In particular, we show that mice colonized with strains carrying deletions of these genes were more effectively sterilized by daily caspofungin treatment relative to mice colonized with the wild-type parental strain. Furthermore, consistent with a role of tolerant cells serving as a reservoir for generating resistant mutations, a reduction in tolerance was associated with a reduction in the emergence of resistant strains. Finally, reduced susceptibility in these strains was due both to the well described FKS-dependent mechanisms and as yet unknown, FKS-independent mechanisms. Together, these results shed light on the importance of cell wall integrity maintenance in echinocandin tolerance and emergence of resistance and lay the foundation for future studies of the factors described herein.

In vitro and in vivo polysaccharides assembly: ultrastructural and cytochemical study of growing plant cell wall components.

1978 ◽  
Vol 36 (2) ◽  
pp. 434-435
Author(s):  
D. Reis ◽  
B. Vian ◽  
J. C. Roland
Keyword(s):  
Cell Wall ◽  
Self Assembly ◽  
Plant Cell Wall ◽  
Higher Plants ◽  
Three Dimensional ◽  
Cytochemical Study ◽  
Wall Components

Wall morphogenesis in higher plants is a problem still open to controversy. Until now the possibility of a transmembrane control and the involvement of microtubules were mostly envisaged. Self-assembly processes have been observed in the case of walls of Chlamydomonas and bacteria. Spontaneous gelling interactions between xanthan and galactomannan from Ceratonia have been analyzed very recently. The present work provides indications that some processes of spontaneous aggregation could occur in higher plants during the formation and expansion of cell wall.Observations were performed on hypocotyl of mung bean (Phaseolus aureus) for which growth characteristics and wall composition have been previously defined.In situ, the walls of actively growing cells (primary walls) show an ordered three-dimensional organization (fig. 1). The wall is typically polylamellate with multifibrillar layers alternately transverse and longitudinal. Between these layers intermediate strata exist in which the orientation of microfibrils progressively rotates. Thus a progressive change in the morphogenetic activity occurs.

scholarly journals Conifers Phytochemicals: A Valuable Forest with Therapeutic Potential

Molecules ◽  
2021 ◽  
Vol 26 (10) ◽  
pp. 3005
Author(s):  
Kanchan Bhardwaj ◽  
Ana Sanches Silva ◽  
Maria Atanassova ◽  
Rohit Sharma ◽  
Eugenie Nepovimova ◽  
...  
Keyword(s):  
Experimental Data ◽  
Potential Role ◽  
Therapeutic Potential ◽  
Fungal Infections ◽  
Cell Damage ◽  
Cancer Growth ◽  
Naturally Occurring ◽  
Antioxidant Effects

Conifers have long been recognized for their therapeutic potential in different disorders. Alkaloids, terpenes and polyphenols are the most abundant naturally occurring phytochemicals in these plants. Here, we provide an overview of the phytochemistry and related commercial products obtained from conifers. The pharmacological actions of different phytochemicals present in conifers against bacterial and fungal infections, cancer, diabetes and cardiovascular diseases are also reviewed. Data obtained from experimental and clinical studies performed to date clearly underline that such compounds exert promising antioxidant effects, being able to inhibit cell damage, cancer growth, inflammation and the onset of neurodegenerative diseases. Therefore, an attempt has been made with the intent to highlight the importance of conifer-derived extracts for pharmacological purposes, with the support of relevant in vitro and in vivo experimental data. In short, this review comprehends the information published to date related to conifers’ phytochemicals and illustrates their potential role as drugs.

Sign in / Sign up

Export Citation Format

Share Document