scholarly journals Vibrio vulnificus Biotype 3 Multifunctional Autoprocessing RTX Toxin Is an Adenylate Cyclase Toxin Essential for Virulence in Mice

2014 ◽  
Vol 82 (5) ◽  
pp. 2148-2157 ◽  
Author(s):  
Kevin J. Ziolo ◽  
Hee-Gon Jeong ◽  
Jayme S. Kwak ◽  
Shuangni Yang ◽  
Robert M. Lavker ◽  
...  
Keyword(s):  
Adenylate Cyclase ◽  
Vibrio Vulnificus ◽  
Infection Model ◽  
High Morbidity ◽  
Wound Infections ◽  
Effector Domain ◽  
Content Type ◽  
Food Borne ◽  
Catalytically Active ◽  
Emergent Pathogen

ABSTRACTVibrio vulnificusis an environmental organism that causes both food-borne and wound infections with high morbidity and mortality in humans. The annual incidence and global distribution of infections associated with this pathogen are increasing with climate change. In the late 1990s, an outbreak of tilapia-associated wound infections in Israel was linked to a previously unrecognized variant ofV. vulnificusdesignated biotype 3. The sudden emergence and clonality of the outbreak suggest that this strain may be a true newly emergent pathogen with novel virulence properties compared to those of otherV. vulnificusstrains. In a subcutaneous infection model to mimic wound infection, the multifunctional autoprocessing RTX (MARTX) toxin of biotype 3 strains was shown to be an essential virulence factor contributing to highly inflammatory skin wounds with severe damage affecting every tissue layer. We conducted a sequencing-based analysis of the MARTX toxin and found that biotype 3 MARTX toxin has an effector domain structure distinct from that of either biotype 1 or biotype 2. Of the two new domains identified, a domain similar toPseudomonas aeruginosaExoY was shown to confer adenylate cyclase activity on the MARTX toxin. This is the first demonstration that the biotype 3 MARTX toxin is essential for virulence and that the ExoY-like MARTX effector domain is a catalytically active adenylate cyclase.

scholarly journals Variable Virulence of Biotype 3Vibrio vulnificusdue to MARTX Toxin Effector Domain Composition

mSphere ◽  
2017 ◽  
Vol 2 (4) ◽  
Author(s):  
Byoung Sik Kim ◽  
Hannah E. Gavin ◽  
Karla J. F. Satchell
Keyword(s):  
Food Chain ◽  
Vibrio Vulnificus ◽  
Infectious Agent ◽  
High Morbidity ◽  
Effector Domain ◽  
Content Type ◽  
Human Food ◽  
Effector Domains ◽  
Human Food Chain ◽  
Natural Hosts

ABSTRACTVibrio vulnificusis an environmental organism that causes septic human infections characterized by high morbidity and mortality. The annual incidence and global distribution of this pathogen are increasing as ocean waters warm. Clinical strains exhibit variations in the primary virulence toxin, suggesting a potential for the emergence of new strains with altered virulence properties. A clonal outbreak of tilapia-associated wound infections in Israel serves as a natural experiment for the sudden emergence of a newV. vulnificusstrain. The effector domain content of the multifunctional autoprocessing RTX (MARTX) toxin of the outbreak-associated biotype 3 (BT3) strains was previously shown to harbor a modification generated by recombination. The modification introduced an actin-induced adenylate cyclase effector domain (ExoY) and an effector domain that disrupts the Golgi organelle (DmX). Here, we report that the exchange of these effector domains for a putative progenitor biotype 1 toxin arrangement produces a toxin that slows the lysis kinetics of targeted epithelial cells but increases cellular rounding phenotypes in response to bacteria. In addition, replacing the biotype 3 toxin variant with the putative progenitor biotype 1 variant renders the resulting strain significantly more virulent in mice. This suggests that the exchange of MARTX effector domains during the emergence of BT3 generated a toxin with reduced toxin potency, resulting in decreased virulence of this outbreak-associated strain. We posit that selection for reduced virulence may serve as a route for this lethal infectious agent to enter the human food chain by allowing it to persist in natural hosts.IMPORTANCEVibrio vulnificusis a serious infection linked to climate change. The virulence capacity of these bacteria can vary by gene exchange, resulting in new variants of the primary virulence toxin. In this study, we tested whether the emergence of an epidemic strain ofV. vulnificuswith a novel toxin variant correlated with a change in virulence. We found that restoring the biotype 3 toxin variant to the putative progenitor-type toxin resulted in dramatically increased virulence, revealing that the emergence of the biotype 3 strain could be linked to virulence reduction. This reduced virulence, previously found also in the biotype 1 strain, suggests that reduced virulence may stimulate outbreaks, as strains have greater capacity to enter the human food chain through reduced impact to environmental hosts.

scholarly journals Staphylococcus aureusImpairs the Function of and Kills Human Dendritic Cells via the LukAB Toxin

mBio ◽  
2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Evelien T. M. Berends ◽  
Xuhui Zheng ◽  
Erin E. Zwack ◽  
Mickaël M. Ménager ◽  
Michael Cammer ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Dendritic Cells ◽  
Adaptive Immunity ◽  
T Cell Activation ◽  
Antigen Presenting Cells ◽  
Infection Model ◽  
High Morbidity ◽  
Content Type ◽  
Human Dendritic Cells ◽  
Antigen Presenting

ABSTRACTStaphylococcus aureusis a human pathogen responsible for high morbidity and mortality worldwide. Recurrent infections with this bacterium are common, suggesting thatS. aureusthwarts the development of sterilizing immunity.S. aureusstrains that cause disease in humans produce up to five different bicomponent toxins (leukocidins) that target and lyse neutrophils, innate immune cells that represent the first line of defense againstS. aureusinfections. However, little is known about the role of leukocidins in blunting adaptive immunity. Here, we explored the effects of leukocidins on human dendritic cells (DCs), antigen-presenting cells required for the development of adaptive immunity. Using anex vivoinfection model of primary human monocyte-derived dendritic cells, we found thatS. aureus, including strains from different clonal complexes and drug resistance profiles, effectively kills DCs despite efficient phagocytosis. Although all purified leukocidins could kill DCs, infections with live bacteria revealed thatS. aureustargets and kills DCs primarily via the activity of leukocidin LukAB. Moreover, using coculture experiments performed with DCs and autologous CD4+T lymphocytes, we found that LukAB inhibits DC-mediated activation and proliferation of primary human T cells. Taken together, the data determined in the study reveal a novel immunosuppressive strategy ofS. aureuswhereby the bacterium blunts the development of adaptive immunity via LukAB-mediated injury of DCs.IMPORTANCEAntigen-presenting cells such as dendritic cells (DCs) fulfill an indispensable role in the development of adaptive immunity by producing proinflammatory cytokines and presenting microbial antigens to lymphocytes to trigger a faster, specific, and long-lasting immune response. Here, we studied the effect ofStaphylococcus aureustoxins on human DCs. We discovered that the leukocidin LukAB hinders the development of adaptive immunity by targeting human DCs. The ability ofS. aureusto blunt the function of DCs could help explain the high frequency of recurrentS. aureusinfections. Taken together, the results from this study suggest that therapeutically targeting theS. aureusleukocidins may boost effective innate and adaptive immune responses by protecting innate leukocytes, enabling proper antigen presentation and T cell activation.

scholarly journals Molecular and Physical Factors That Influence Attachment of Vibrio vulnificus to Chitin

2015 ◽  
Vol 81 (18) ◽  
pp. 6158-6165 ◽  
Author(s):  
Tiffany C. Williams ◽  
Mesrop Ayrapetyan ◽  
James D. Oliver
Keyword(s):  
Quorum Sensing ◽  
Vibrio Vulnificus ◽  
The United States ◽  
Type Iv Pili ◽  
Negative Regulator ◽  
Physical Factors ◽  
Wound Infections ◽  
Environmental Persistence ◽  
Content Type ◽  
Type Iv

ABSTRACTThe human pathogenVibrio vulnificusis the leading cause of seafood-related deaths in the United States. Strains are genotyped on the basis of alleles that correlate with isolation source, with clinical (C)-genotype strains being more often implicated in disease and environmental (E)-genotype strains being more frequently isolated from oysters and estuarine waters. Previously, we have shown that the ecologically distinct C- and E-genotype strains ofV. vulnificusdisplay different degrees of chitin attachment, with C-genotype strains exhibiting reduced attachment relative to their E-genotype strain counterparts. We identified type IV pili to be part of the molecular basis for this observed genotypic variance, as E-genotype strains exhibit higher levels of expression of these genes than C-genotype strains. Here, we used a C-genotype quorum-sensing (QS) mutant to demonstrate that quorum sensing is a negative regulator of type IV pilus expression, which results in decreased chitin attachment. Furthermore, calcium depletion reduced E-genotype strain attachment to chitin, which suggests that calcium is necessary for proper functioning of the type IV pili in E-genotype strains. We also found that starvation or dormancy can alter the efficiency of chitin attachment, which has significant implications for the environmental persistence ofV. vulnificus. With the increasing incidence of wound infections caused byV. vulnificus, we investigated a subset of E-genotype strains isolated from human wound infections and discovered that they attached to chitin in a manner more similar to that of C-genotype strains. This study enhances our understanding of the molecular and physical factors that mediate chitin attachment inV. vulnificus, providing insight into the mechanisms that facilitate the persistence of this pathogen in its native environment.

scholarly journals Tornadic Shear Stress Induces a Transient, Calcineurin-Dependent Hypervirulent Phenotype in Mucorales Molds

mBio ◽  
2020 ◽  
Vol 11 (3) ◽  
Author(s):  
Sebastian Wurster ◽  
Alexander M. Tatara ◽  
Nathaniel D. Albert ◽  
Ashraf S. Ibrahim ◽  
Joseph Heitman ◽  
...  
Keyword(s):  
Shear Stress ◽  
Mechanical Stress ◽  
Fungal Growth ◽  
High Energy ◽  
Infection Model ◽  
High Morbidity ◽  
Sequencing Analysis ◽  
Loss Of Function ◽  
Content Type ◽  
The Impact

ABSTRACT Trauma-related necrotizing myocutaneous mucormycosis (NMM) has a high morbidity and mortality in victims of combat-related injuries, geometeorological disasters, and severe burns. Inspired by the observation that several recent clusters of NMM have been associated with extreme mechanical forces (e.g., during tornados), we studied the impact of mechanical stress on Mucoralean biology and virulence in a Drosophila melanogaster infection model. In contrast to other experimental procedures to exert mechanical stress, tornadic shear challenge (TSC) by magnetic stirring induced a hypervirulent phenotype in several clinically relevant Mucorales species but not in Aspergillus or Fusarium. Whereas fungal growth rates, morphogenesis, and susceptibility to noxious environments or phagocytes were not altered by TSC, soluble factors released in the supernatant of shear-challenged R. arrhizus spores rendered static spores hypervirulent. Consistent with a rapid decay of TSC-induced hypervirulence, minimal transcriptional changes were revealed by comparative RNA sequencing analysis of static and shear-challenged Rhizopus arrhizus. However, inhibition of the calcineurin/heat shock protein 90 (hsp90) stress response circuitry by cyclosporine and tanespimycin abrogated the increased pathogenicity of R. arrhizus spores following TSC. Similarly, calcineurin loss-of-function mutants of Mucor circinelloides displayed no increased virulence capacity in flies after undergoing TSC. Collectively, these results establish that TSC induces hypervirulence specifically in Mucorales and point out the calcineurin/hsp90 pathway as a key orchestrator of this phenotype. Our findings invite future studies of topical calcineurin inhibitor treatment of wounds as an adjunct mitigation strategy for NMM following high-energy trauma. IMPORTANCE Given the limited efficacy of current medical treatments in trauma-related necrotizing mucormycosis, there is a dire need to better understand the Mucoralean pathophysiology in order to develop novel strategies to counteract fungal tissue invasion following severe trauma. Here, we describe that tornadic shear stress challenge transiently induces a hypervirulent phenotype in various pathogenic Mucorales species but not in other molds known to cause wound infections. Pharmacological and genetic inhibition of calcineurin signaling abrogated hypervirulence in shear stress-challenged Mucorales, encouraging further evaluation of (topical) calcineurin inhibitors to improve therapeutic outcomes of NMM after combat-related blast injuries or violent storms.

scholarly journals Pancreatic Amylase Is an Environmental Signal for Regulation of Biofilm Formation and Host Interaction in Campylobacter jejuni

2015 ◽  
Vol 83 (12) ◽  
pp. 4884-4895 ◽  
Author(s):  
Waheed Jowiya ◽  
Katja Brunner ◽  
Sherif Abouelhadid ◽  
Haitham A. Hussain ◽  
Sean P. Nair ◽  
...  
Keyword(s):  
Campylobacter Jejuni ◽  
Biofilm Formation ◽  
Galleria Mellonella ◽  
Infection Model ◽  
Pancreatic Amylase ◽  
Content Type ◽  
Host Interaction ◽  
Food Borne ◽  
Epithelial Cell Lines

Campylobacter jejuniis a commensal bacterium in the intestines of animals and birds and a major cause of food-borne gastroenteritis in humans worldwide. Here we show that exposure to pancreatic amylase leads to secretion of an α-dextran byC. jejuniand that a secreted protease, Cj0511, is required. Exposure ofC. jejunito pancreatic amylase promotes biofilm formationin vitro, increases interaction with human epithelial cell lines, increases virulence in theGalleria mellonellainfection model, and promotes colonization of the chicken ileum. We also show that exposure to pancreatic amylase protectsC. jejunifrom stress conditionsin vitro, suggesting that the induced α-dextran may be important during transmission between hosts. This is the first evidence that pancreatic amylase functions as an interkingdom signal in an enteric microorganism.

scholarly journals The Makes Caterpillars Floppy (MCF)-Like Domain of Vibrio vulnificus Induces Mitochondrion-Mediated Apoptosis

2015 ◽  
Vol 83 (11) ◽  
pp. 4392-4403 ◽  
Author(s):  
Shivangi Agarwal ◽  
Yeuming Zhu ◽  
David R. Gius ◽  
Karla J. F. Satchell
Keyword(s):  
Cellular Proliferation ◽  
Vibrio Vulnificus ◽  
Lethal Factor ◽  
Cell Types ◽  
Host Cells ◽  
Intrinsic Apoptosis ◽  
Apoptosis Pathway ◽  
Effector Domain ◽  
Content Type ◽  
Intrinsic Apoptosis Pathway

ABSTRACTThe multifunctional-autoprocessing repeats-in-toxin (MARTXVv) toxin ofVibrio vulnificusplays a significant role in the pathogenesis of this bacterium through delivery of up to five effector domains to the host cells. Previous studies have established that the MARTXVvtoxin is linked toV. vulnificusdependent induction of apoptosis, but the region of the large multifunction protein essential for this activity was not previously identified. Recently, we showed that the Makes Caterpillar Floppy-like MARTX effector domain (MCFVv) is an autoproteolytic cysteine protease that induces rounding of various cell types. In this study, we demonstrate that cell rounding induced by MCFVvis coupled to reduced metabolic rate and inhibition of cellular proliferation. Moreover, delivery of MCFVvinto host cells either as a fusion to the N-terminal fragment of anthrax toxin lethal factor or when naturally delivered as aV. vulnificusMARTX toxin led to loss of mitochondrial membrane potential, release of cytochromec, activation of Bax and Bak, and processing of caspases and poly-(ADP-ribose) polymerase (PARP-γ). These studies specifically link the MCFVveffector domain to induction of the intrinsic apoptosis pathway byV. vulnificus.

scholarly journals Chitin-Induced Carbotype Conversion in Vibrio vulnificus

2011 ◽  
Vol 79 (8) ◽  
pp. 3195-3203 ◽  
Author(s):  
Jana Neiman ◽  
Yunzhi Guo ◽  
Dean A. Rowe-Magnus
Keyword(s):  
Capsular Polysaccharide ◽  
Vibrio Vulnificus ◽  
Natural Transformation ◽  
Extracellular Dna ◽  
Lytic Phage ◽  
Wound Infections ◽  
Bacterial Sepsis ◽  
General Role ◽  
Content Type ◽  
Genetic Mechanisms

ABSTRACTAs an etiological agent of bacterial sepsis and wound infections,Vibrio vulnificusis unique among theVibrionaceae. The most intensely studied of its virulence factors is the capsular polysaccharide (CPS). Over 100 CPS types have been identified, yet little is known about the genetic mechanisms that drive such diversity. Chitin, the second-most-abundant polysaccharide in nature, is known to induce competence inVibriospecies. Here, we show that the frequency of chitin-induced transformation inV. vulnificusvaries by strain and that (GlcNAc)2is the shortest chitin-derived polymer capable of inducing competence. Transformation frequencies (TFs) increased 8-fold when mixed-culture biofilms were exposed to a strain-specific lytic phage, suggesting that the lysis of dead cells during lytic infection increased the amount of extracellular DNA within the biofilm that was available for transfer. Furthermore, we show thatV. vulnificuscan undergo chitin-dependent carbotype conversion following the uptake and recombination of completecpsloci from exogenous genomic DNA (gDNA). The acquisition of a partial locus was also demonstrated when internal regions of homology between the endogenous and exogenous loci existed. This suggested that the same mechanism governing the transfer of completecpsloci also contributed to their evolution by generating novel combinations of CPS biosynthesis genes. Since no evidence thatcpsloci were preferentially acquired during natural transformation (random transposon-tagged DNA was readily taken up in chitin transformation assays) exists, the phenomenon of chitin-induced transformation likely plays an important but general role in the evolution of this genetically promiscuous genus.

scholarly journals A Proof-of-Concept Study of the Efficacy of Systemically Administered Polymyxins in Mouse Burn Wound Infection Caused by Multidrug-Resistant Gram-Negative Pathogens

2018 ◽  
Vol 62 (5) ◽  
Author(s):  
Yu-Wei Lin ◽  
Ke Chen ◽  
Jiping Wang ◽  
Tony Velkov ◽  
Qi Tony Zhou ◽  
...  
Keyword(s):  
Bacterial Load ◽  
Polymyxin B ◽  
Multidrug Resistant ◽  
Infection Model ◽  
Wound Infections ◽  
Proof Of Concept ◽  
Burn Wound ◽  
Gram Negative ◽  
Content Type ◽  
Therapeutic Benefits

ABSTRACTThe efficacy of subcutaneously administered polymyxins against burn wound infections caused byPseudomonas aeruginosa,Acinetobacter baumannii, andKlebsiella pneumoniaewas examined in a murine infection model. Subcutaneously administered colistin and polymyxin B (30 mg/kg thrice daily) achieved a ≥2-log10reduction in the bacterial load forP. aeruginosaandA. baumanniiinfections, whereas wound infections byK. pneumoniaewere less responsive (<1-log10reduction). This study highlights the potential therapeutic benefits of parenteral polymyxins for treating burn wound infections.

scholarly journals Determination of the frequency of carbapenemase producing Klebsiella pneumoniae isolates in Dhaka city, Bangladesh

2013 ◽  
Vol 2 (1) ◽  
pp. 28-30 ◽  
Author(s):  
Nawshad Hayder ◽  
Zahidul Hasan ◽  
Sadia Afrin ◽  
Rashed Noor
Keyword(s):  
Urinary Tract Infection ◽  
Urinary Tract ◽  
Klebsiella Pneumoniae ◽  
Respiratory Diseases ◽  
High Morbidity ◽  
Wound Infections ◽  
Dhaka City ◽  
Carbapenem Resistant ◽  
Global Health Problem

Resistance of Klebsiella pneumoniae against carbapenem, imparted by the presence of carbapenemase, is an emerging global health problem with high morbidity and mortality. Thus, the present study attempted to detect the frequency of carbapenemase producing K. pneumoniae in Dhaka city of Bangladesh and thereby determine the health risk associated with their presence. A total of 647 K. pneumoniae isolates were detected from 2800 patients with urinary tract infection, bacterimia, wound infections and respiratory diseases. Thirty one carbapenem resistant isolates were found to harbor K. pneumoniae carbapenemase (KPC) through modified Hodge test. The KPC positive isolates were then subjected to the study of antibiogram and showed resistance against all the ß-lactam antibiotics along with carbapenems, while they were sensitive against colistin. Additionally, 287 isolates were found to be extended-spectrum ?-lactamases (ESBLs) positive apart from the KPC positive ones. DOI: http://dx.doi.org/10.3329/sjm.v2i1.15210 Stamford Journal of Microbiology, Vol.2(1) 2012: 28-30

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