scholarly journals Invasion mechanisms of Gram-positive pathogenic cocci

2007 ◽  
Vol 98 (09) ◽  
pp. 488-496 ◽  
Author(s):  
Patric Nitsche-Schmitz ◽  
Manfred Rohde ◽  
Gursharan Chhatwal
Keyword(s):  
Surface Proteins ◽  
Host Cells ◽  
Human Pathogens ◽  
Gram Positive ◽  
Bacterial Surface ◽  
Surface Receptors ◽  
Major Threat ◽  
Invasion Mechanisms ◽  
Invasive Infections ◽  
Gram Positive Cocci

SummaryGram-positive cocci are important human pathogens. Streptococci and staphylococci in particular are a major threat to human health,since they cause a variety of serious invasive infections. Their invasion into normally sterile sites of the host depends on elaborated bacterial mechanisms that involve adhesion to the host tissue, its degradation, internalisation by host cells, and passage through epithelia and endothelia. Interactions of bacterial surface proteins with proteins of the host’s extracellular matrix as well as with cell surface receptors are crucial factors in these processes, and some of the key mechanisms are similar in many pathogenic Gram-positive cocci.Therapies that interfere with these mechanisms may become efficient alternatives to today’s antibiotic treatments.

scholarly journals Heterologously Expressed Staphylococcus aureusFibronectin-Binding Proteins Are Sufficient for Invasion of Host Cells

2000 ◽  
Vol 68 (12) ◽  
pp. 6871-6878 ◽  
Author(s):  
Bhanu Sinha ◽  
Patrice Francois ◽  
Yok-Ai Que ◽  
Muzaffar Hussain ◽  
Christine Heilmann ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Binding Proteins ◽  
Surface Protein ◽  
Latex Agglutination ◽  
Surface Proteins ◽  
Host Cells ◽  
Gram Positive ◽  
Fibronectin Receptor ◽  
293 Cells ◽  
Accessible Surface

ABSTRACT Staphylococcus aureus invasion of mammalian cells, including epithelial, endothelial, and fibroblastic cells, critically depends on fibronectin bridging between S. aureusfibronectin-binding proteins (FnBPs) and the host fibronectin receptor integrin α5β1 (B. Sinha et al., Cell. Microbiol. 1:101–117, 1999). However, it is unknown whether this mechanism is sufficient for S. aureus invasion. To address this question, various S. aureus adhesins (FnBPA, FnBPB, and clumping factor [ClfA]) were expressed in Staphylococcus carnosus and Lactococcus lactis subsp.cremoris. Both noninvasive gram-positive microorganisms are genetically distinct from S. aureus, lack any knownS. aureus surface protein, and do not bind fibronectin. Transformants of S. carnosus and L. lactisharboring plasmids coding for various S. aureus surface proteins (FnBPA, FnBPB, and ClfA) functionally expressed adhesins (as determined by bacterial clumping in plasma, specific latex agglutination, Western ligand blotting, and binding to immobilized and soluble fibronectin). FnBPA or FnBPB but not of ClfA conferred invasiveness to S. carnosus and L. lactis. Invasion of 293 cells by transformants was comparable to that of strongly invasive S. aureus strain Cowan 1. Binding of soluble and immobilized fibronectin paralleled invasiveness, demonstrating that the amount of accessible surface FnBPs is rate limiting. Thus, S. aureus FnBPs confer invasiveness to noninvasive, apathogenic gram-positive cocci. Furthermore, FnBP-coated polystyrene beads were internalized by 293 cells, demonstrating that FnBPs are sufficient for invasion of host cells without the need for (S. aureus-specific) coreceptors.

scholarly journals Structures of the surface exposed proteins of Gram positive bacteria

2014 ◽  
Vol 70 (a1) ◽  
pp. C432-C432
Author(s):  
George Minasov ◽  
Salvatore Nocadello ◽  
Ekaterina Filippova ◽  
Andrei Halavaty ◽  
Wayne Anderson
Keyword(s):  
Cell Wall ◽  
Infectious Diseases ◽  
Bacillus Anthracis ◽  
Structural Genomics ◽  
Drug Targets ◽  
Morphological Changes ◽  
Target Selection ◽  
Surface Proteins ◽  
Human Pathogens ◽  
Gram Positive

The Center for Structural Genomics for Infectious Diseases (CSGID) applies structural genomics approaches to biomedically important proteins from human pathogens. It also provides the infectious disease community with a high throughput pipeline for structure determination that carries out all steps of the process, from target selection through structure deposition. Target proteins include drug targets, essential enzymes, virulence factors and vaccine candidates. The CSGID has deposited over 680 structures in the Protein Data Bank. The proteins that are exposed on the surface of Gram positive bacterial pathogens (including Staphylococcus aureus, Bacillus anthracis, Listeria monocytogenes, Streptococcus species and Clostridium species) have been one focus area for the CSGID. So far, the structures of more than 55 of these proteins have been determined. The surface proteins are important in the interactions between the pathogen and its host, but many of them are as yet functionally uncharacterized. Among the examples that will be presented is the Bacillus anthracis SpoIID protein. SpoIID is part of a coordinated cell wall degradation machine that is essential for sporulation and the morphological changes involved. It represents a new family of lytic transglycosylases that degrade the glycan strands of the peptidoglycan cell wall. The two active site clefts in the dimeric enzyme include residues from both subunits, suggesting that the dimer is required for activity. This project has been funded in whole or in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contracts No. HHSN272200700058C and HHSN272201200026C.

scholarly journals Cyclic Dimeric GMP Signaling Regulates Intracellular Aggregation, Sessility, and Growth of Ehrlichia chaffeensis

2011 ◽  
Vol 79 (10) ◽  
pp. 3905-3912 ◽  
Author(s):  
Yumi Kumagai ◽  
Junji Matsuo ◽  
Zhihui Cheng ◽  
Yoshihiro Hayakawa ◽  
Yasuko Rikihisa
Keyword(s):  
Serine Protease ◽  
Serine Proteases ◽  
Matrix Protein ◽  
Response Regulator ◽  
Bacterial Biofilm ◽  
Surface Proteins ◽  
Host Cells ◽  
Ehrlichia Chaffeensis ◽  
Content Type ◽  
Bacterial Surface

ABSTRACTCyclic dimeric GMP (c-di-GMP), a bacterial second messenger, is known to regulate bacterial biofilm and sessility. Replication of an obligatory intracellular pathogen,Ehrlichia chaffeensis, is characterized by formation of bacterial aggregates called morulae inside membrane-bound inclusions. WhenE. chaffeensismatures into an infectious form, morulae become loose to allow bacteria to exit from host cells to infect adjacent cells.E. chaffeensisexpresses a sensor kinase, PleC, and a cognate response regulator, PleD, which can produce c-di-GMP. A hydrophobic c-di-GMP antagonist, 2′-O-di(tert-butyldimethysilyl)-c-di-GMP (CDGA) inhibitsE. chaffeensisinternalization into host cells by facilitating degradation of some bacterial surface proteins via endogenous serine proteases. In the present study, we found that PleC and PleD were upregulated synchronously during exponential growth of bacteria, concomitant with increased morula size. While CDGA did not affect host cells, when infected cells were treated with CDGA, bacterial proliferation was inhibited, morulae became less compact, and the intracellular movement of bacteria was enhanced. Concurrently, CDGA treatment facilitated the extracellular release of bacteria with lower infectivity than those spontaneously released from sham-treated cells. Addition of CDGA to isolated inclusions induced dispersion of the morulae, degradation of an inclusion matrix protein TRP120, and bacterial intrainclusion movement, all of which were blocked by a serine protease inhibitor. These results suggest that c-di-GMP signaling regulates aggregation and sessility ofE. chaffeensiswithin the inclusion through stabilization of matrix proteins by preventing the serine protease activity, which is associated with bacterial intracellular proliferation and maturation.

scholarly journals Synthesis and Biological Evaluation of Novel Indole-Derived Thioureas

Molecules ◽  
2018 ◽  
Vol 23 (10) ◽  
pp. 2554 ◽  
Author(s):  
Giuseppina Sanna ◽  
Silvia Madeddu ◽  
Gabriele Giliberti ◽  
Sandra Piras ◽  
Marta Struga ◽  
...  
Keyword(s):  
Rna Viruses ◽  
Wide Spectrum ◽  
Biological Evaluation ◽  
Significant Inhibition ◽  
Molecular Structures ◽  
Human Pathogens ◽  
Topoisomerase Iv ◽  
Gram Positive ◽  
Hiv 1 ◽  
Gram Positive Cocci

A series of 2-(1H-indol-3-yl)ethylthiourea derivatives were prepared by condensation of 2-(1H-indol-3-yl)ethanamine with appropriate aryl/alkylisothiocyanates in anhydrous media. The structures of the newly synthesized compounds were confirmed by spectroscopic analysis and the molecular structures of 8 and 28 were confirmed by X-ray crystallography. All obtained compounds were tested for antimicrobial activity against Gram-positive cocci, Gram-negative rods and for antifungal activity. Microbiological evaluation was carried out over 20 standard strains and 30 hospital strains. Compound 6 showed significant inhibition against Gram-positive cocci and had inhibitory effect on the S. aureus topoisomerase IV decatenation activity and S. aureus DNA gyrase supercoiling activity. Compounds were tested for cytotoxicity and antiviral activity against a large panel of DNA and RNA viruses, including HIV-1 and other several important human pathogens. Interestingly, derivative 8 showed potent activity against HIV-1 wild type and variants bearing clinically relevant mutations. Newly synthesized tryptamine derivatives showed also a wide spectrum activity, proving to be active against positive- and negative-sense RNA viruses.

scholarly journals Contribution of Human Thrombospondin-1 to the Pathogenesis of Gram-Positive Bacteria

2019 ◽  
Vol 11 (4) ◽  
pp. 303-315 ◽  
Author(s):  
Ulrike Binsker ◽  
Thomas P. Kohler ◽  
Sven Hammerschmidt
Keyword(s):  
Extracellular Matrix ◽  
Human Platelets ◽  
Surface Proteins ◽  
Matrix Proteins ◽  
Matricellular Proteins ◽  
Gram Positive ◽  
Bacterial Surface ◽  
Gram Positive Bacteria ◽  
Thrombospondin 1 ◽  
Successful Colonization

A successful colonization of different compartments of the human host requires multifactorial contacts between bacterial surface proteins and host factors. Extracellular matrix proteins and matricellular proteins such as thrombospondin-1 play a pivotal role as adhesive substrates to ensure a strong interaction with pathobionts like the Gram-positive Streptococcus pneumoniae and Staphylococcus aureus. The human glycoprotein thrombospondin-1 is a component of the extracellular matrix and is highly abundant in the bloodstream during bacteremia. Human platelets secrete thrombospondin-1, which is then acquired by invading pathogens to facilitate colonization and immune evasion. Gram-positive bacteria express a broad spectrum of surface-exposed proteins, some of which also recognize thrombospondin-1. This review highlights the importance of thrombospondin-1 as an adhesion substrate to facilitate colonization, and we summarize the variety of thrombospondin-1-binding proteins of S. pneumoniae and S. aureus.

scholarly journals Covalent host-targeting by thioester domains of Gram-positive pathogens

2014 ◽  
Vol 70 (a1) ◽  
pp. C848-C848
Author(s):  
Miriam Walden ◽  
John Edwards ◽  
Aleksandra Dziewulska ◽  
Uli Schwarz-Linek ◽  
Mark Banfield
Keyword(s):  
Cell Surface ◽  
Host Cell ◽  
Molecular Mechanisms ◽  
Cell Attachment ◽  
Surface Proteins ◽  
Host Cells ◽  
Covalent Attachment ◽  
Gram Positive ◽  
Covalent Bonds ◽  
Isopeptide Bonds

Gram-positive pathogens are a major concern to global health, with increasing resistance to antimicrobials and the lack of preventative therapeutics. Understanding how these bacteria interact with host cells is vital for the development of novel strategies to combat disease. One of the most crucial steps in infection is adhesion to the host cell. The discovery of complex cell-surface associated proteins, such as pili, has advanced our knowledge of this interaction, however the precise molecular mechanisms underlying this process remain unclear. Structural studies of pili revealed the presence of highly unusual intramolecular covalent bonds between amino acid side chains. These include isopeptide bonds between Lys and Asp/Asn residues, conferring mechanical strength, thermal stability and resistance to proteases [1,2]. In Streptococcus pyogenes pili, the adhesin Spy0125 (or Cpa) interacts with the host cell. It comprises three domains, two of which contain stabilising isopeptide bonds [2,3]. Intriguingly, the third domain contains an extremely rare thioester bond, between a Cys and a Gln residue. A Cys to Ala mutation results in a 75% reduction in adhesion, suggesting that this internal linkage may mediate direct attachment [3]. We have now discovered putative thioester domains (TEDs) in cell-surface proteins of several clinically important pathogens. The only other example of an internal thioester is found in complement proteins, where the reactive bond enables the formation of covalent attachment to pathogens. The presence of these bonds in bacterial proteins suggests the possibility of an as-yet uncharacterised, conserved mechanism of covalent host cell attachment. For a selection of pathogens, we have used mass spectrometry and crystallography to confirm the presence of the covalent link between the Cys and Gln residues within the TEDs. Furthermore, we have identified putative host cell targets of TEDs and confirmed covalent linkages between the TED and the target.

scholarly journals Discovery of Fibrillar Adhesins across Bacterial Species

2020 ◽  
Author(s):  
Vivian Monzon ◽  
Aleix Lafita ◽  
Alex Bateman
Keyword(s):  
Cell Surface ◽  
Bacterial Species ◽  
Domain Architecture ◽  
Surface Proteins ◽  
Host Cells ◽  
Bacterial Surface ◽  
Bacterial Phyla ◽  
C Terminus ◽  
Wide Range ◽  
Bacterial Proteomes

AbstractBackgroundFibrillar adhesins are long multidomain proteins attached at the cell surface and composed of at least one adhesive domain and multiple tandemly repeated domains, which build an elongated stalk that projects the adhesive domain beyond the bacterial cell surface. They are an important yet understudied class of proteins that mediate interactions of bacteria with their environment. This study aims to characterize fibrillar adhesins in a wide range of bacterial phyla and to identify new fibrillar adhesin-like proteins to improve our understanding of host-bacteria interactions.ResultsBy careful search for fibrillar adhesins in the literature and by computational analysis we identified 75 stalk domains and 24 adhesive domains. Based on the presence of these domains in the UniProt Reference Proteomes database, we identified and analysed 3,388 fibrillar adhesin-like proteins across species of the most common bacterial phyla. We found that the bacterial proteomes with the highest fraction of fibrillar adhesins include several known pathogens. We further enumerate the adhesive and stalk domain combinations found in nature and demonstrate that fibrillar adhesins have complex and variable domain architectures, which differ across species. By analysing the domain architecture of fibrillar adhesins we show that in Gram positive bacteria adhesive domains are mostly positioned at the N-terminus of the protein with the cell surface anchor at the C-terminus, while their positions are more variable in Gram negative bacteria. We provide an open repository of fibrillar adhesin-like proteins and domains to facilitate downstream studies of this class of bacterial surface proteins.ConclusionThis study provides a domain-based characterization of fibrillar adhesins and demonstrates that they are widely found across the main bacterial phyla. We have discovered numerous novel fibrillar adhesins and improved the understanding of how pathogens might adhere to and subsequently invade into host cells.

scholarly journals Mycobacterial surface-associated ESX-1 virulence factors play a role in mycobacterial adherence and invasion into lung epithelial cells

2020 ◽  
Author(s):  
Yanqing Bao ◽  
Qi Zhang ◽  
Lin Wang ◽  
Javier Aguilera ◽  
Salvador Vazquez Reyes ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Gene Knockout ◽  
Tween 80 ◽  
Cytolytic Activity ◽  
Lung Epithelial Cells ◽  
Host Cells ◽  
Bacterial Surface ◽  
Surface Receptors ◽  
Neutral Ph ◽  
Lung Epithelial

AbstractEsxA has long been recognized as an important virulence factor of Mycobacterium tuberculosis (Mtb) that plays an essential role in Mtb cytosolic translocation by penetrating phagosomal membranes with its acidic pH-dependent membrane permeabilizing activity (MPA). Since the reported cytolytic activity of EsxA at neutral pH is controversial, in the present study we have obtained direct evidence that it is the residual ASB-14, a detergent used in EsxA purification, but not EsxA that causes cytolysis at neutral pH. Besides, we have also found that the exogenously added EsxA was internalized into lung epithelial cells (WI-26) and inserted into the host membranes, and these processes could be blocked by cytochalasin D and bafilomycin A. This indicates that EsxA is bound by host surface receptors and internalized into acidic endosomal compartments. This observation has intrigued us to investigate the role of EsxA in mycobacterial adherence and invasion in host cells. Interestingly, compared to the Mycobacterium marinum (Mm) wild type strain, the Mm strain with deletion of the esxBA operon (MmΔEsxA:B) had a lower adherence but a higher invasion in WI-26 cells. More interestingly, either inducible knockdown of EsxAB or removal of the bacterial surface-associated EsxAB by Tween-80 exhibited opposite results compared to gene knockout. Finally, the surface-associated EsxA is correlated to mycobacterial virulence. Together, the present study has shown for the first time that EsxA is internalized into the host cells and inserts into the host membranes, and mycobacterial surface-associated EsxAB plays an important role in mycobacterial adherence and invasion in host cells, which warrants further investigation.

scholarly journals Two Monoclonal Antibodies with Defined Epitopes of P44 Major Surface Proteins Neutralize Anaplasma phagocytophilum by Distinct Mechanisms

2006 ◽  
Vol 74 (3) ◽  
pp. 1873-1882 ◽  
Author(s):  
Xueqi Wang ◽  
Takane Kikuchi ◽  
Yasuko Rikihisa
Keyword(s):  
Monoclonal Antibodies ◽  
Anaplasma Phagocytophilum ◽  
Outer Membrane Proteins ◽  
Critical Role ◽  
Hypervariable Region ◽  
Passive Immunization ◽  
Amino Acid Sequences ◽  
Surface Proteins ◽  
Host Cells ◽  
Bacterial Surface

ABSTRACT Anaplasma phagocytophilum is an obligatory intracellular bacterium that causes human granulocytic anaplasmosis. The polymorphic 44-kDa major outer membrane proteins of A. phagocytophilum are dominant antigens recognized by patients and infected animals. However, the ability of anti-P44 antibody to neutralize the infection has been unclear due to a mixture of P44 proteins with diverse hypervariable region amino acid sequences expressed by a given bacterial population and lack of epitope-defined antibodies. Monoclonal antibodies (MAbs) 5C11 and 3E65 are directed to different domains of P44 proteins, the N-terminal conserved region and P44-18 central hypervariable region, respectively. Passive immunization with either MAb 5C11 or 3E65 partially protects mice from infection with A. phagocytophilum. In the present study, we demonstrated that the two monoclonal antibodies recognize bacterial surface-exposed epitopes of naturally folded P44 proteins and mapped these epitopes to specific peptide sequences. The two MAbs almost completely blocked the infection of the A. phagocytophilum population that predominantly expressed P44-18 in HL-60 cells by distinct mechanisms: MAb 5C11 blocked the binding, but MAb 3E65 did not block binding or internalization. Instead, MAb 3E65 inhibited internalized A. phagocytophilum to develop into microcolonies called morulae. Some plasma from experimentally infected horses and mice reacted with these two epitopes. Taken together, these data indicate the presence of at least two distinct bacterial surface-exposed neutralization epitopes in P44 proteins. The results indicate that antibodies directed to certain epitopes of P44 proteins have a critical role in inhibiting A. phagocytophilum infection of host cells.

scholarly journals Discovery of fibrillar adhesins across bacterial species

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Vivian Monzon ◽  
Aleix Lafita ◽  
Alex Bateman
Keyword(s):  
Cell Surface ◽  
Bacterial Species ◽  
Domain Architecture ◽  
Surface Proteins ◽  
Bacterial Surface ◽  
Bacterial Phyla ◽  
Gram Positive Bacteria ◽  
Invasion Mechanisms ◽  
C Terminus ◽  
Wide Range

Abstract Background Fibrillar adhesins are long multidomain proteins that form filamentous structures at the cell surface of bacteria. They are an important yet understudied class of proteins composed of adhesive and stalk domains that mediate interactions of bacteria with their environment. This study aims to characterize fibrillar adhesins in a wide range of bacterial phyla and to identify new fibrillar adhesin-like proteins to improve our understanding of host-bacteria interactions. Results Through careful literature and computational searches, we identified 82 stalk and 27 adhesive domain families in fibrillar adhesins. Based on the presence of these domains in the UniProt Reference Proteomes database, we identified and analysed 3,542 fibrillar adhesin-like proteins across species of the most common bacterial phyla. We further enumerate the adhesive and stalk domain combinations found in nature and demonstrate that fibrillar adhesins have complex and variable domain architectures, which differ across species. By analysing the domain architecture of fibrillar adhesins, we show that in Gram positive bacteria, adhesive domains are mostly positioned at the N-terminus and cell surface anchors at the C-terminus of the protein, while their positions are more variable in Gram negative bacteria. We provide an open repository of fibrillar adhesin-like proteins and domains to enable further studies of this class of bacterial surface proteins. Conclusion This study provides a domain-based characterization of fibrillar adhesins and demonstrates that they are widely found in species across the main bacterial phyla. We have discovered numerous novel fibrillar adhesins and improved our understanding of pathogenic adhesion and invasion mechanisms.

Sign in / Sign up

Export Citation Format

Share Document