scholarly journals DNA Delivery and Genomic Integration into Mammalian Target Cells through Type IV A and B Secretion Systems of Human Pathogens

2017 ◽  
Vol 8 ◽  
Author(s):  
Dolores L. Guzmán-Herrador ◽  
Samuel Steiner ◽  
Anabel Alperi ◽  
Coral González-Prieto ◽  
Craig R. Roy ◽  
...  
Keyword(s):  
Dna Delivery ◽  
Target Cells ◽  
Human Pathogens ◽  
Secretion Systems ◽  
Genomic Integration ◽  
Type Iv

scholarly journals Two type IV secretion systems with different functions in Burkholderia cenocepacia K56-2

Microbiology ◽  
2009 ◽  
Vol 155 (12) ◽  
pp. 4005-4013 ◽  
Author(s):  
Ruifu Zhang ◽  
John J. LiPuma ◽  
Carlos F. Gonzalez
Keyword(s):  
Type Iv Secretion ◽  
Burkholderia Cenocepacia ◽  
Target Cells ◽  
Secretion Systems ◽  
Type Iv ◽  
Plasmid Mobilization ◽  
Type Iv Secretion Systems ◽  
Derivative Plasmid ◽  
Chromosome Ii ◽  
Bacterial Type

Bacterial type IV secretion systems (T4SS) perform two fundamental functions related to pathogenesis: the delivery of effector molecules to eukaryotic target cells, and genetic exchange. Two T4SSs have been identified in Burkholderia cenocepacia K56-2, a representative of the ET12 lineage of the B. cepacia complex (Bcc). The plant tissue watersoaking (Ptw) T4SS encoded on a resident 92 kb plasmid is a chimera composed of VirB/D4 and F-specific subunits, and is responsible for the translocation of effector(s) that have been linked to the Ptw phenotype. The bc-VirB/D4 system located on chromosome II displays homology to the VirB/D4 T4SS of Agrobacterium tumefaciens. In contrast to the Ptw T4SS, the bc-VirB/D4 T4SS was found to be dispensable for Ptw effector(s) secretion, but was found to be involved in plasmid mobilization. The fertility inhibitor Osa did not affect the secretion of Ptw effector(s) via the Ptw system, but did disrupt the mobilization of a RSF1010 derivative plasmid.

scholarly journals Peptidomimetic Small Molecules Disrupt Type IV Secretion System Activity in Diverse Bacterial Pathogens

mBio ◽  
2016 ◽  
Vol 7 (2) ◽  
Author(s):  
Carrie L. Shaffer ◽  
James A. D. Good ◽  
Santosh Kumar ◽  
K. Syam Krishnan ◽  
Jennifer A. Gaddy ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Small Molecules ◽  
Bacterial Pathogens ◽  
Effector Proteins ◽  
Type Iv Secretion ◽  
Target Cells ◽  
Effector Protein ◽  
Secretion Systems ◽  
Type Iv ◽  
H Pylori

ABSTRACT Bacteria utilize complex type IV secretion systems (T4SSs) to translocate diverse effector proteins or DNA into target cells. Despite the importance of T4SSs in bacterial pathogenesis, the mechanism by which these translocation machineries deliver cargo across the bacterial envelope remains poorly understood, and very few studies have investigated the use of synthetic molecules to disrupt T4SS-mediated transport. Here, we describe two synthetic small molecules (C10 and KSK85) that disrupt T4SS-dependent processes in multiple bacterial pathogens. Helicobacter pylori exploits a pilus appendage associated with the cag T4SS to inject an oncogenic effector protein (CagA) and peptidoglycan into gastric epithelial cells. In H. pylori , KSK85 impedes biogenesis of the pilus appendage associated with the cag T4SS, while C10 disrupts cag T4SS activity without perturbing pilus assembly. In addition to the effects in H. pylori , we demonstrate that these compounds disrupt interbacterial DNA transfer by conjugative T4SSs in Escherichia coli and impede vir T4SS-mediated DNA delivery by Agrobacterium tumefaciens in a plant model of infection. Of note, C10 effectively disarmed dissemination of a derepressed IncF plasmid into a recipient bacterial population, thus demonstrating the potential of these compounds in mitigating the spread of antibiotic resistance determinants driven by conjugation. To our knowledge, this study is the first report of synthetic small molecules that impair delivery of both effector protein and DNA cargos by diverse T4SSs. IMPORTANCE Many human and plant pathogens utilize complex nanomachines called type IV secretion systems (T4SSs) to transport proteins and DNA to target cells. In addition to delivery of harmful effector proteins into target cells, T4SSs can disseminate genetic determinants that confer antibiotic resistance among bacterial populations. In this study, we sought to identify compounds that disrupt T4SS-mediated processes. Using the human gastric pathogen H. pylori as a model system, we identified and characterized two small molecules that prevent transfer of an oncogenic effector protein to host cells. We discovered that these small molecules also prevented the spread of antibiotic resistance plasmids in E. coli populations and diminished the transfer of tumor-inducing DNA from the plant pathogen A. tumefaciens to target cells. Thus, these compounds are versatile molecular tools that can be used to study and disarm these important bacterial machines.

scholarly journals Biological Diversity of Prokaryotic Type IV Secretion Systems

2009 ◽  
Vol 73 (4) ◽  
pp. 775-808 ◽  
Author(s):  
Cristina E. Alvarez-Martinez ◽  
Peter J. Christie
Keyword(s):  
Target Cell ◽  
Biological Diversity ◽  
Cell Interaction ◽  
Type Iv Secretion ◽  
Target Cells ◽  
Secretion Systems ◽  
Extracellular Milieu ◽  
Type Iv ◽  
Type Iv Secretion Systems ◽  
Cell Envelopes

SUMMARY Type IV secretion systems (T4SS) translocate DNA and protein substrates across prokaryotic cell envelopes generally by a mechanism requiring direct contact with a target cell. Three types of T4SS have been described: (i) conjugation systems, operationally defined as machines that translocate DNA substrates intercellularly by a contact-dependent process; (ii) effector translocator systems, functioning to deliver proteins or other macromolecules to eukaryotic target cells; and (iii) DNA release/uptake systems, which translocate DNA to or from the extracellular milieu. Studies of a few paradigmatic systems, notably the conjugation systems of plasmids F, R388, RP4, and pKM101 and the Agrobacterium tumefaciens VirB/VirD4 system, have supplied important insights into the structure, function, and mechanism of action of type IV secretion machines. Information on these systems is updated, with emphasis on recent exciting structural advances. An underappreciated feature of T4SS, most notably of the conjugation subfamily, is that they are widely distributed among many species of gram-negative and -positive bacteria, wall-less bacteria, and the Archaea. Conjugation-mediated lateral gene transfer has shaped the genomes of most if not all prokaryotes over evolutionary time and also contributed in the short term to the dissemination of antibiotic resistance and other virulence traits among medically important pathogens. How have these machines adapted to function across envelopes of distantly related microorganisms? A survey of T4SS functioning in phylogenetically diverse species highlights the biological complexity of these translocation systems and identifies common mechanistic themes as well as novel adaptations for specialized purposes relating to the modulation of the donor-target cell interaction.

scholarly journals T4SS Effector Protein Prediction with Deep Learning

Data ◽  
2019 ◽  
Vol 4 (1) ◽  
pp. 45 ◽  
Author(s):  
Koray Açıcı ◽  
Tunç Aşuroğlu ◽  
Çağatay Erdaş ◽  
Hasan Oğul
Keyword(s):  
Deep Learning ◽  
Extraction Methods ◽  
Effector Proteins ◽  
Machine Learning Algorithms ◽  
Host Cells ◽  
Correct Prediction ◽  
Human Pathogens ◽  
Secretion Systems ◽  
Type Iv ◽  
Protein Prediction

Extensive research has been carried out on bacterial secretion systems, as they can pass effector proteins directly into the cytoplasm of host cells. The correct prediction of type IV protein effectors secreted by T4SS is important, since they are known to play a noteworthy role in various human pathogens. Studies on predicting T4SS effectors involve traditional machine learning algorithms. In this work we included a deep learning architecture, i.e., a Convolutional Neural Network (CNN), to predict IVA and IVB effectors. Three feature extraction methods were utilized to represent each protein as an image and these images fed the CNN as inputs in our proposed framework. Pseudo proteins were generated using ADASYN algorithm to overcome the imbalanced dataset problem. We demonstrated that our framework predicted all IVA effectors correctly. In addition, the sensitivity performance of 94.2% for IVB effector prediction exhibited our framework’s ability to discern the effectors in unidentified proteins.

scholarly journals iT4SE-EP: Accurate Identification of Bacterial Type IV Secreted Effectors by Exploring Evolutionary Features from Two PSI-BLAST Profiles

Molecules ◽  
2021 ◽  
Vol 26 (9) ◽  
pp. 2487
Author(s):  
Haitao Han ◽  
Chenchen Ding ◽  
Xin Cheng ◽  
Xiuzhi Sang ◽  
Taigang Liu
Keyword(s):  
Evolutionary Information ◽  
Support Vector ◽  
Target Cells ◽  
Secretion Systems ◽  
Accurate Identification ◽  
Feature Selection Technique ◽  
Type Iv ◽  
Evolutionary Features ◽  
Wide Range ◽  
Encoding Strategies

Many gram-negative bacteria use type IV secretion systems to deliver effector molecules to a wide range of target cells. These substrate proteins, which are called type IV secreted effectors (T4SE), manipulate host cell processes during infection, often resulting in severe diseases or even death of the host. Therefore, identification of putative T4SEs has become a very active research topic in bioinformatics due to its vital roles in understanding host-pathogen interactions. PSI-BLAST profiles have been experimentally validated to provide important and discriminatory evolutionary information for various protein classification tasks. In the present study, an accurate computational predictor termed iT4SE-EP was developed for identifying T4SEs by extracting evolutionary features from the position-specific scoring matrix and the position-specific frequency matrix profiles. First, four types of encoding strategies were designed to transform protein sequences into fixed-length feature vectors based on the two profiles. Then, the feature selection technique based on the random forest algorithm was utilized to reduce redundant or irrelevant features without much loss of information. Finally, the optimal features were input into a support vector machine classifier to carry out the prediction of T4SEs. Our experimental results demonstrated that iT4SE-EP outperformed most of existing methods based on the independent dataset test.

scholarly journals Role of Bacterial Secretion Systems and Effector Proteins – Insight into the Pathogenicity Mechanisms in Aeromonas

2020 ◽  
Author(s):  
Joanna Matys ◽  
Anna Turska-Szewczuk ◽  
Anna Sroka-Bartnicka
Keyword(s):  
Virulence Factors ◽  
Secretion System ◽  
Effector Proteins ◽  
Host Cells ◽  
Target Cells ◽  
Virulence Determinants ◽  
Secretion Systems ◽  
Variable Expression ◽  
Type Iv ◽  
T3ss Effector

Gram-negative bacteria have developed several nanomachine channels known as type II, III, IV and VI secretion systems that enable export of effector proteins/toxins from the cytosol across the outer membrane to target host cells. Protein secretion systems are critical to bacterial virulence and interactions with other organisms. Aeromonas utilize various secretion machines e.g. two-step T2SS, a Sec-dependent system as well as one-step, Sec-independent T3SS and T6SS systems to transport effector proteins/toxins and virulence factors. Type III secretion system (T3SS) is considered the dominant virulence system in Aeromonas. The activity of bacterial T3SS effector proteins most often leads to disorders in signalling pathways and reorganization of the cell cytoskeleton. There are also scientific reports on the pathogenicity mechanism associated with host cell apopotosis/pyroptosis resulting from secretion of a cytotoxic enterotoxin, i.e. the Act protein, by the T2SS secretion system and an effector protein Hcp by the T6SS system. Type IV secretion system (T4SS) is the system which translocate protein substrates, protein-DNA complexes and DNA into eukaryotic or bacterial target cells. In this paper, the contribution of virulence determinants involved in the pathogenicity potential of Aeromonas is discussed. Considering that the variable expression of virulence factors has a decisive impact on the differences observed in the virulence of particular species of microorganisms, it is important to assess the correlation between bacterial pathogenicity and their virulence-associated genes.

scholarly journals Functional and Topological Characterization of Novel Components of the comB DNA Transformation Competence System in Helicobacter pylori

2006 ◽  
Vol 188 (3) ◽  
pp. 882-893 ◽  
Author(s):  
Arno Karnholz ◽  
Claudia Hoefler ◽  
Stefan Odenbreit ◽  
Wolfgang Fischer ◽  
Dirk Hofreuter ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Target Cells ◽  
Dna Uptake ◽  
Secretion Systems ◽  
Computer Prediction ◽  
Type Iv ◽  
Essential Components ◽  
H Pylori ◽  
Transformation Competence ◽  
Competence System

ABSTRACT Helicobacter pylori is one of the most diverse bacterial species known. A rational basis for this genetic variation may be provided by its natural competence for genetic transformation and high-frequency recombination. Many bacterial competence systems have homology with proteins that are involved in the assembly of type IV pili and type II secretion systems. In H. pylori, DNA uptake relies on a transport system related to type IV secretion systems (T4SS) designated the comB system. The prototype of a T4SS in Agrobacterium tumefaciens consists of 11 VirB proteins and VirD4, which form the core unit necessary for the delivery of single proteins or large nucleoprotein complexes into target cells. In the past we identified proteins ComB4 and ComB7 through ComB10 as being involved in the process of DNA uptake in H. pylori. In this study we identified and functionally characterized further (T4SS-homologous) components of the comB transformation competence system. By combining computer prediction modeling, experimental topology determination, generation of knockout strains, and genetic complementation studies we identified ComB2, ComB3, and ComB6 as essential components of the transformation apparatus, structurally and functionally homologous to VirB2, VirB3, and VirB6, respectively. comB2, comB3, and comB4 are organized as a separate operon. Thus, for the H. pylori comB system, all T4SS core components have been identified except for homologues to VirB1, VirD4, VirB5, and VirB11.

scholarly journals ATPase Activity and Oligomeric State of TrwK, the VirB4 Homologue of the Plasmid R388 Type IV Secretion System

2008 ◽  
Vol 190 (15) ◽  
pp. 5472-5479 ◽  
Author(s):  
Ignacio Arechaga ◽  
Alejandro Peña ◽  
Sandra Zunzunegui ◽  
María del Carmen Fernández-Alonso ◽  
Germán Rivas ◽  
...  
Keyword(s):  
Atpase Activity ◽  
Analytical Ultracentrifugation ◽  
Type Iv Secretion ◽  
Conjugative Plasmid ◽  
Target Cells ◽  
Secretion Systems ◽  
Oligomeric State ◽  
Type Iv ◽  
Catalytically Active

ABSTRACT Type IV secretion systems (T4SS) mediate the transfer of DNA and protein substrates to target cells. TrwK, encoded by the conjugative plasmid R388, is a member of the VirB4 family, comprising the largest and most conserved proteins of T4SS. VirB4 was suggested to be an ATPase involved in energizing pilus assembly and substrate transport. However, conflicting experimental evidence concerning VirB4 ATP hydrolase activity was reported. Here, we demonstrate that TrwK is able to hydrolyze ATP in vitro in the absence of its potential macromolecular substrates and other T4SS components. The kinetic parameters of its ATPase activity have been characterized. The TrwK oligomerization state was investigated by analytical ultracentrifugation and electron microscopy, and its effects on ATPase activity were analyzed. The results suggest that the hexameric form of TrwK is the catalytically active state, much like the structurally related protein TrwB, the conjugative coupling protein.

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