Genes, Pathways, and Mechanisms Involved in the Virulence of Mucorales

The order Mucorales is a group of ancient fungi with limited tools for gene manipulation. The main consequence of this manipulation unwillingness is the limited knowledge about its biology compared to other fungal groups. However, the emerging of mucormycosis, a fungal infection caused by Mucorales, is attracting the medical spotlight in recent years because the treatments available are not efficient in reducing the high mortality associated with this disease. The result of this renewed interest in Mucorales and mucormycosis is an extraordinarily productive effort to unveil their secrets during the last decade. In this review, we describe the most compelling advances related to the genetic study of virulence factors, pathways, and molecular mechanisms developed in these years. The use of a few genetic study models has allowed the characterization of virulence factors in Mucorales that were previously described in other pathogens, such as the uptake iron systems, the mechanisms of dimorphism, and azole resistances. More importantly, recent studies are identifying new genes and mechanisms controlling the pathogenic potential of Mucorales and their interactions with the host, offering new alternatives to develop specific strategies against mucormycosis.

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Coagulase Negative Staphylococci (CoNS): A Review

Journal of Pharmaceutical Research International ◽

10.9734/jpri/2021/v33i52b33630 ◽

2021 ◽

pp. 304-315

Author(s):

Suvarna Sande

Keyword(s):

Virulence Factors ◽

Molecular Mechanisms ◽

Methicillin Resistance ◽

Clinical Importance ◽

Diagnostic Techniques ◽

Cross Resistance ◽

Coagulase Negative Staphylococcus ◽

Screening Methods ◽

Coagulase Negative Staphylococci ◽

Pathogenic Potential

Coagulase-negative staphylococcus (CoNS) has gained more importance as pathogenic organism for infections in both human and animals. CoNS are especially prevalent in immunocompromised patients, critically ill patients, patients having invasive medical devices. The incidence of CoNS varied across different geographic locations in humans and animals. Also, there are varying antibiotic resistance patterns observed in CoNS species, with high methicillin resistance and cross resistance against many antibiotics. Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus xylosus are the most commonly reported species in various studies. Various virulence factors in CoNS are responsible for enhanced pathogenicity. Because of advancement in diagnostic techniques understanding of molecular mechanisms of CoNS pathogenicity is possible. Recent advances in identification and typing methods, virulence screening methods will help to assess true pathogenic potential of CoNS species. This review focuses on various CoNS species, their identification and virulence factors and clinical importance.

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Searching for virulence factors in the non-pathogenic parasite to humans Leishmania tarentolae

Parasitology ◽

10.1017/s0031182009005873 ◽

2009 ◽

Vol 136 (7) ◽

pp. 723-735 ◽

Cited By ~ 23

Author(s):

H. AZIZI ◽

K. HASSANI ◽

Y. TASLIMI ◽

H. SHATERI NAJAFABADI ◽

B. PAPADOPOULOU ◽

...

Keyword(s):

Virulence Factors ◽

Pathogenic Species ◽

Protein Alignment ◽

Pathogenic Potential ◽

Leishmania Tarentolae ◽

New Horizons ◽

Intracellular Parasites ◽

Pathogenic Parasite ◽

Degree Of Similarity

SUMMARYLeishmania protozoa are obligate intracellular parasites that reside in the phagolysosome of host macrophages and cause a large spectrum of pathologies to humans known as leishmaniases. The outcome of the disease is highly dependent on the parasite species and on its ascribed virulence factors and the immune status of the host. Characterization of the genome composition of non-pathogenic species could ultimately open new horizons in Leishmania developmental biology and also the disease monitoring. Here, we provide evidence that the lizard non-pathogenic to humans Leishmania tarentolae species expresses an Amastin-like gene, cysteine protease B (CPB), lipophosphoglycan LPG3 and the leishmanolysin GP63, genes well-known for their potential role in the parasite virulence. These genes were expressed at levels comparable to those in L. major and L. infantum both at the level of mRNA and protein. Alignment of the L. tarentolae proteins with their counterparts in the pathogenic species demonstrated that the degree of similarity varied from 59% and 60% for Amastin, 89% for LPG3 and 71% and 68% for CPB, in L. major and L. infantum, respectively. Interestingly, the A2 gene, expressed specifically by the L. donovani complex which promotes visceralization, was absent in L. tarentolae. These findings suggest that the lack of pathogenicity in L. tarentolae is not associated with known virulence genes such as LPG3, CPB, GP63 and Amastin, and that other factors either unique to L. tarentolae or missing from this species may be responsible for the non-pathogenic potential of this lizard parasite.

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Xyloglucan processing machinery in Xanthomonas pathogens and its role in the transcriptional activation of virulence factors

Nature Communications ◽

10.1038/s41467-021-24277-4 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Plinio S. Vieira ◽

Isabela M. Bonfim ◽

Evandro A. Araujo ◽

Ricardo R. Melo ◽

Augusto R. Lima ◽

...

Keyword(s):

Virulence Factors ◽

Transcriptional Activation ◽

Molecular Mechanisms ◽

Model Organism ◽

Citrus Canker ◽

Effector Proteins ◽

Glycoside Hydrolases ◽

Host Cells ◽

System A ◽

Enzymatic Machinery

AbstractXyloglucans are highly substituted and recalcitrant polysaccharides found in the primary cell walls of vascular plants, acting as a barrier against pathogens. Here, we reveal that the diverse and economically relevant Xanthomonas bacteria are endowed with a xyloglucan depolymerization machinery that is linked to pathogenesis. Using the citrus canker pathogen as a model organism, we show that this system encompasses distinctive glycoside hydrolases, a modular xyloglucan acetylesterase and specific membrane transporters, demonstrating that plant-associated bacteria employ distinct molecular strategies from commensal gut bacteria to cope with xyloglucans. Notably, the sugars released by this system elicit the expression of several key virulence factors, including the type III secretion system, a membrane-embedded apparatus to deliver effector proteins into the host cells. Together, these findings shed light on the molecular mechanisms underpinning the intricate enzymatic machinery of Xanthomonas to depolymerize xyloglucans and uncover a role for this system in signaling pathways driving pathogenesis.

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Genetic mapping and transcriptomic characterization of a new fuzzless-tufted cottonseed mutant

G3 Genes|Genome|Genetics ◽

10.1093/g3journal/jkaa042 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Qian-Hao Zhu ◽

Warwick Stiller ◽

Philippe Moncuquet ◽

Stuart Gordon ◽

Yuman Yuan ◽

...

Keyword(s):

Molecular Mechanisms ◽

Agronomic Traits ◽

Gene Families ◽

Mutant Phenotype ◽

Wild Type ◽

Calcium Dependent ◽

Dependent Protein ◽

Flanking Region ◽

Comparative Transcriptomic Analysis

Abstract Fiber mutants are unique and valuable resources for understanding the genetic and molecular mechanisms controlling initiation and development of cotton fibers that are extremely elongated single epidermal cells protruding from the seed coat of cottonseeds. In this study, we reported a new fuzzless-tufted cotton mutant (Gossypium hirsutum) and showed that fuzzless-tufted near-isogenic lines (NILs) had similar agronomic traits and a higher ginning efficiency compared to their recurrent parents with normal fuzzy seeds. Genetic analysis revealed that the mutant phenotype is determined by a single incomplete dominant locus, designated N5. The mutation was fine mapped to an approximately 250-kb interval containing 33 annotated genes using a combination of bulked segregant sequencing, SNP chip genotyping, and fine mapping. Comparative transcriptomic analysis using 0–6 days post-anthesis (dpa) ovules from NILs segregating for the phenotypes of fuzzless-tufted (mutant) and normal fuzzy cottonseeds (wild-type) uncovered candidate genes responsible for the mutant phenotype. It also revealed that the flanking region of the N5 locus is enriched with differentially expressed genes (DEGs) between the mutant and wild-type. Several of those DEGs are members of the gene families with demonstrated roles in cell initiation and elongation, such as calcium-dependent protein kinase and expansin. The transcriptome landscape of the mutant was significantly reprogrammed in the 6 dpa ovules and, to a less extent, in the 0 dpa ovules, but not in the 2 and 4 dpa ovules. At both 0 and 6 dpa, the reprogrammed mutant transcriptome was mainly associated with cell wall modifications and transmembrane transportation, while transcription factor activity was significantly altered in the 6 dpa mutant ovules. These results imply a similar molecular basis for initiation of lint and fuzz fibers despite certain differences.

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A Concerted Action of UBA5 C-Terminal Unstructured Regions Is Important for Transfer of Activated UFM1 to UFC1

International Journal of Molecular Sciences ◽

10.3390/ijms22147390 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7390

Author(s):

Nicole Wesch ◽

Frank Löhr ◽

Natalia Rogova ◽

Volker Dötsch ◽

Vladimir V. Rogov

Keyword(s):

Cellular Localization ◽

Molecular Mechanisms ◽

Biochemical Characterization ◽

Effective Interaction ◽

Regulatory Region ◽

Titration Calorimetry ◽

Enzymatic Reactions ◽

Cellular Processes ◽

Mechanism Of Interaction

Ubiquitin fold modifier 1 (UFM1) is a member of the ubiquitin-like protein family. UFM1 undergoes a cascade of enzymatic reactions including activation by UBA5 (E1), transfer to UFC1 (E2) and selective conjugation to a number of target proteins via UFL1 (E3) enzymes. Despite the importance of ufmylation in a variety of cellular processes and its role in the pathogenicity of many human diseases, the molecular mechanisms of the ufmylation cascade remains unclear. In this study we focused on the biophysical and biochemical characterization of the interaction between UBA5 and UFC1. We explored the hypothesis that the unstructured C-terminal region of UBA5 serves as a regulatory region, controlling cellular localization of the elements of the ufmylation cascade and effective interaction between them. We found that the last 20 residues in UBA5 are pivotal for binding to UFC1 and can accelerate the transfer of UFM1 to UFC1. We solved the structure of a complex of UFC1 and a peptide spanning the last 20 residues of UBA5 by NMR spectroscopy. This structure in combination with additional NMR titration and isothermal titration calorimetry experiments revealed the mechanism of interaction and confirmed the importance of the C-terminal unstructured region in UBA5 for the ufmylation cascade.

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The Power of Yeast in Modelling Human Nuclear Mutations Associated with Mitochondrial Diseases

Genes ◽

10.3390/genes12020300 ◽

2021 ◽

Vol 12 (2) ◽

pp. 300

Author(s):

Camilla Ceccatelli Berti ◽

Giulia di Punzio ◽

Cristina Dallabona ◽

Enrico Baruffini ◽

Paola Goffrini ◽

...

Keyword(s):

Molecular Mechanisms ◽

Mitochondrial Diseases ◽

Yeast Saccharomyces Cerevisiae ◽

Genome Data ◽

New Genes ◽

Eukaryotic Organism ◽

Novel Variants ◽

Therapeutic Molecules ◽

Nuclear Mutations

The increasing application of next generation sequencing approaches to the analysis of human exome and whole genome data has enabled the identification of novel variants and new genes involved in mitochondrial diseases. The ability of surviving in the absence of oxidative phosphorylation (OXPHOS) and mitochondrial genome makes the yeast Saccharomyces cerevisiae an excellent model system for investigating the role of these new variants in mitochondrial-related conditions and dissecting the molecular mechanisms associated with these diseases. The aim of this review was to highlight the main advantages offered by this model for the study of mitochondrial diseases, from the validation and characterisation of novel mutations to the dissection of the role played by genes in mitochondrial functionality and the discovery of potential therapeutic molecules. The review also provides a summary of the main contributions to the understanding of mitochondrial diseases emerged from the study of this simple eukaryotic organism.

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High-resolution view of HIV-1 reverse transcriptase initiation complexes and inhibition by NNRTI drugs

Nature Communications ◽

10.1038/s41467-021-22628-9 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Betty Ha ◽

Kevin P. Larsen ◽

Jingji Zhang ◽

Ziao Fu ◽

Elizabeth Montabana ◽

...

Keyword(s):

Reverse Transcriptase ◽

Viral Entry ◽

Reverse Transcription ◽

Molecular Mechanisms ◽

Dissociation Kinetics ◽

Structural Mechanism ◽

Medium Resolution ◽

Kinetics Of ◽

Hiv 1

AbstractReverse transcription of the HIV-1 viral RNA genome (vRNA) is an integral step in virus replication. Upon viral entry, HIV-1 reverse transcriptase (RT) initiates from a host tRNALys3 primer bound to the vRNA genome and is the target of key antivirals, such as non-nucleoside reverse transcriptase inhibitors (NNRTIs). Initiation proceeds slowly with discrete pausing events along the vRNA template. Despite prior medium-resolution structural characterization of reverse transcriptase initiation complexes (RTICs), higher-resolution structures of the RTIC are needed to understand the molecular mechanisms that underlie initiation. Here we report cryo-EM structures of the core RTIC, RTIC–nevirapine, and RTIC–efavirenz complexes at 2.8, 3.1, and 2.9 Å, respectively. In combination with biochemical studies, these data suggest a basis for rapid dissociation kinetics of RT from the vRNA–tRNALys3 initiation complex and reveal a specific structural mechanism of nucleic acid conformational stabilization during initiation. Finally, our results show that NNRTIs inhibit the RTIC and exacerbate discrete pausing during early reverse transcription.

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Hemolysis in the spleen drives erythrocyte turnover

Blood ◽

10.1182/blood.2020005351 ◽

2020 ◽

Author(s):

Thomas robert leon Klei ◽

Jill Jasmine Dalimot ◽

Benjamin Nota ◽

Martijn Veldthuis ◽

Erik Mul ◽

...

Keyword(s):

Molecular Mechanisms ◽

Matrix Proteins ◽

Human Spleen ◽

Erythrocyte Adhesion ◽

Subsequent Degradation ◽

Macrophage Subpopulations ◽

Senescent Erythrocytes ◽

Red Pulp

Red pulp macrophages of the spleen mediate turnover of billions of senescent erythrocytes per day. However, the molecular mechanisms involved in sequestration of senescent erythrocytes, their recognition and their subsequent degradation by red pulp macrophages remain unclear. In this study we provide evidence that the splenic environment is of substantial importance in facilitating erythrocyte turnover through induction of hemolysis. Upon isolating human spleen red pulp macrophages we noted a substantial lack of macrophages that were in the process of phagocytosing intact erythrocytes. Detailed characterization of erythrocyte and macrophage subpopulations from human spleen tissue led to the identification of erythrocytes that are devoid of hemoglobin, so-called erythrocyte ghosts. By in vivo imaging and transfusion experiments we further confirmed that senescent erythrocytes that are retained in the spleen are subject to hemolysis. Additionally, we show that erythrocyte adhesion molecules, which are specifically activated on aged erythrocytes, cause senescent erythrocytes to interact with extracellular matrix proteins that are exposed within the splenic architecture. Such adhesion molecule-driven retention of senescent erythrocytes, under low shear conditions, was found to result in steady shrinkage of the cell and ultimately resulted in hemolysis. In contrast to intact senescent erythrocytes, the remnant erythrocyte ghost shells were prone to recognition and breakdown by red pulp macrophages. These data identify hemolysis as a key event in the turnover of senescent erythrocytes, which alters our current understanding of how erythrocyte degradation is regulated.

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Novel Gene Regulation in Normal and Abnormal Spermatogenesis

Cells ◽

10.3390/cells10030666 ◽

2021 ◽

Vol 10 (3) ◽

pp. 666

Author(s):

Li Du ◽

Wei Chen ◽

Zixin Cheng ◽

Si Wu ◽

Jian He ◽

...

Keyword(s):

Gene Regulation ◽

Leydig Cells ◽

Molecular Mechanisms ◽

New Technologies ◽

Genetic Regulation ◽

Myoid Cells ◽

Epigenetic Factors ◽

Future Directions ◽

New Genes ◽

Human Spermatogenesis

Spermatogenesis is a complex and dynamic process which is precisely controlledby genetic and epigenetic factors. With the development of new technologies (e.g., single-cell RNA sequencing), increasingly more regulatory genes related to spermatogenesis have been identified. In this review, we address the roles and mechanisms of novel genes in regulating the normal and abnormal spermatogenesis. Specifically, we discussed the functions and signaling pathways of key new genes in mediating the proliferation, differentiation, and apoptosis of rodent and human spermatogonial stem cells (SSCs), as well as in controlling the meiosis of spermatocytes and other germ cells. Additionally, we summarized the gene regulation in the abnormal testicular microenvironment or the niche by Sertoli cells, peritubular myoid cells, and Leydig cells. Finally, we pointed out the future directions for investigating the molecular mechanisms underlying human spermatogenesis. This review could offer novel insights into genetic regulation in the normal and abnormal spermatogenesis, and it provides new molecular targets for gene therapy of male infertility.

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Deficiency of the onco-miRNA cluster, miR-106b∼25, causes oligozoospermia and the cooperative action of miR-106b∼25 and miR-17∼92 is required to maintain male fertility

MHR Basic science of reproductive medicine ◽

10.1093/molehr/gaaa027 ◽

2020 ◽

Vol 26 (6) ◽

pp. 389-401

Author(s):

Alicia Hurtado ◽

Rogelio Palomino ◽

Ina Georg ◽

Miguel Lao ◽

Francisca M Real ◽

...

Keyword(s):

Male Fertility ◽

Molecular Mechanisms ◽

Mirna Cluster ◽

Knock Out ◽

Cooperative Action ◽

Mouse Mutants ◽

New Genes ◽

Mirna Clusters ◽

Testicular Histology ◽

And Function

Abstract The identification of new genes involved in sexual development and gonadal function as potential candidates causing male infertility is important for both diagnostic and therapeutic purposes. Deficiency of the onco-miRNA cluster miR-17∼92 has been shown to disrupt spermatogenesis, whereas mutations in its paralog cluster, miR-106b∼25, that is expressed in the same cells, were reported to have no effect on testis development and function. The aim of this work is to determine the role of these two miRNA clusters in spermatogenesis and male fertility. For this, we analyzed miR-106b∼25 and miR-17∼92 single and double mouse mutants and compared them to control mice. We found that miR-106b∼25 knock out testes show reduced size, oligozoospermia and altered spermatogenesis. Transcriptomic analysis showed that multiple molecular pathways are deregulated in these mutant testes. Nevertheless, mutant males conserved normal fertility even when early spermatogenesis and other functions were disrupted. In contrast, miR-17∼92+/−; miR-106b∼25−/− double mutants showed severely disrupted testicular histology and significantly reduced fertility. Our results indicate that miR-106b∼25 and miR-17∼92 ensure accurate gene expression levels in the adult testis, keeping them within the required thresholds. They play a crucial role in testis homeostasis and are required to maintain male fertility. Hence, we have identified new candidate genetic factors to be screened in the molecular diagnosis of human males with reproductive disorders. Finally, considering the well-known oncogenic nature of these two clusters and the fact that patients with reduced fertility are more prone to testicular cancer, our results might also help to elucidate the molecular mechanisms linking both pathologies.

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