scholarly journals Virulence Factors of Clostridioides (Clostridium) difficile Linked to Recurrent Infections

2019 ◽  
Vol 2019 ◽  
pp. 1-7
Author(s):  
Laura Tijerina-Rodríguez ◽  
Licet Villarreal-Treviño ◽  
Rayo Morfín-Otero ◽  
Adrián Camacho-Ortíz ◽  
E. Garza-González
Keyword(s):  
Virulence Factors ◽  
Toxin Production ◽  
Negative Regulator ◽  
Binary Toxin ◽  
Recurrent Infections ◽  
Accessory Gene ◽  
Accessory Gene Regulator ◽  
Cell Internalization ◽  
Adhesion Efficiency ◽  
First Recurrence

From 20 to 30% of Clostridioides (Clostridium) difficile infection (CDI), patients might develop recurrence of the infection (RCDI) and, after the first recurrence, the risk of further episodes increases up to 60%. Several bacterial virulence factors have been associated with RCDI, including the elevated production of toxins A and B, the presence of a binary toxin CDT, and mutations in the negative regulator of toxin expression, tcdC. Additional factors have shown to regulate toxin production and virulence in C. difficile in RCDI, including the accessory-gene regulator agr, which acts as a positive switch for toxin transcription. Furthermore, adhesion and motility-associated factors, such as Cwp84, SlpA, and flagella, have shown to increase the adhesion efficiency to host epithelia, cell internalization, and the formation of biofilm. Finally, biofilm confers to C. difficile protection from antibiotics and acts as a reservoir for spores that allow the persistence of the infection in the host. In this review, we describe the key virulence factors of C. difficile that have been associated with recurrent infections.

scholarly journals Finding of Agr Phase Variants in Staphylococcus aureus

mBio ◽  
2019 ◽  
Vol 10 (4) ◽  
Author(s):  
Vishal Gor ◽  
Aya J. Takemura ◽  
Masami Nishitani ◽  
Masato Higashide ◽  
Veronica Medrano Romero ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Virulence Factors ◽  
Phase Variation ◽  
Accessory Gene ◽  
Content Type ◽  
Accessory Gene Regulator ◽  
Immune Mediated ◽  
A Minor ◽  
First Time ◽  
Phase Variants

ABSTRACT Staphylococcus aureus is an important human pathogen whose success is largely attributed to its vast arsenal of virulence factors that facilitate its invasion into, and survival within, the human host. The expression of these virulence factors is controlled by the quorum sensing accessory gene regulator (Agr) system. However, a large proportion of clinical S. aureus isolates are consistently found to have a mutationally inactivated Agr system. These mutants have a survival advantage in the host but are considered irreversible mutants. Here we show, for the first time, that a fraction of Agr-negative mutants can revert their Agr activity. By serially passaging Agr-negative strains and screening for phenotypic reversion of hemolysis and subsequent sequencing, we identified two mutational events responsible for reversion: a genetic duplication plus inversion event and a poly(A) tract alteration. Additionally, we demonstrate that one clinical Agr-negative methicillin-resistant S. aureus (MRSA) isolate could reproducibly generate Agr-revertant colonies with a poly(A) tract genetic mechanism. We also show that these revertants activate their Agr system upon phagocytosis. We propose a model in which a minor fraction of Agr-negative S. aureus strains are phase variants that can revert their Agr activity and may act as a cryptic insurance strategy against host-mediated stress. IMPORTANCE Staphylococcus aureus is responsible for a broad range of infections. This pathogen has a vast arsenal of virulence factors at its disposal, but avirulent strains are frequently isolated as the cause of clinical infections. These isolates have a mutated agr locus and have been believed to have no evolutionary future. Here we show that a fraction of Agr-negative strains can repair their mutated agr locus with mechanisms resembling phase variation. The agr revertants sustain an Agr OFF state as long as they exist as a minority but can activate their Agr system upon phagocytosis. These revertant cells might function as a cryptic insurance strategy to survive immune-mediated host stress that arises during infection.

scholarly journals Prevalence of Agr phase variants in Staphylococcus aureus

2020 ◽  
Vol 2 (7A) ◽  
Author(s):  
Vishal Gor ◽  
Mitsuaki Hoshi ◽  
Aya Takemura ◽  
Masato Higashide ◽  
Veronica Romero ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Quorum Sensing ◽  
Virulence Factors ◽  
Human Pathogen ◽  
Accessory Gene ◽  
Accessory Gene Regulator ◽  
Inversion Event ◽  
First Time ◽  
Phase Variants ◽  
Phenotypic Reversion

Staphylococcus aureus is an important human pathogen whose success is largely attributed to its vast arsenal of virulence factors that facilitate its invasion into, and survival within, the human host. The expression of these virulence factors is controlled by the quorum sensing Accessory Gene Regulator (Agr) system. However, a large proportion of clinical S. aureus isolates are consistently found to have a mutationally inactivated Agr system. These mutants have a survival advantage in the host but are considered irreversible mutants. Here we show, for the first time, that a fraction of Agr-negative mutants can revert their Agr activity. By serially passaging Agr negative strains and screening for phenotypic reversion of haemolysis and subsequent sequencing, we identified two mutational events responsible for reversion: a genetic duplication plus inversion event and a poly(A) tract alteration. Additionally, we demonstrate that one clinical Agr-negative MRSA isolate could reproducibly generate Agr-revertant colonies with a poly(A) tract genetic mechanism. We also show that these revertants activate their Agr system upon phagocytosis. To assess the significance of our findings we screened a series of primary clinical isolates, which had undergone minimal handling post-isolation, and successfully identified a fraction which were Agr phase variants. Taken together, we propose a model where some Agr-negative S. aureus strains are phase variants who can revert their Agr activity and may act as a cryptic insurance strategy against host-mediated stress.

scholarly journals Generation of Virulence Factor Variants in Staphylococcus aureus Biofilms

2007 ◽  
Vol 189 (22) ◽  
pp. 7961-7967 ◽  
Author(s):  
Jeremy M. Yarwood ◽  
Kara M. Paquette ◽  
Ilya B. Tikh ◽  
Esther M. Volper ◽  
E. Peter Greenberg
Keyword(s):  
Staphylococcus Aureus ◽  
Virulence Factors ◽  
Hemolytic Activity ◽  
Bacterial Species ◽  
Phase Variation ◽  
Accessory Gene ◽  
Altered Expression ◽  
Sensing System ◽  
Accessory Gene Regulator ◽  
Different Strains

ABSTRACT Several serious diseases are caused by biofilm-associated Staphylococcus aureus. Colonial variants occur in biofilms of other bacterial species, and S. aureus variants are frequently isolated from biofilm-associated infections. Thus, we studied the generation of variants with altered expression of virulence factors in S. aureus biofilms. We observed that the number of variants found in biofilms, as measured by hemolytic activity, varied for different strains. Further study of hemolytic activity and signaling by the accessory gene regulator (Agr) quorum-sensing system in one S. aureus strain revealed three primary biofilm subpopulations: nonhemolytic (Agr deficient), hemolytic (Agr positive), and hyperhemolytic (also Agr positive). The nonhemolytic variant became the numerically dominant subpopulation in the biofilm. The nonhemolytic variant phenotype was stable and heritable, indicating a genetic perturbation, whereas the hyperhemolytic phenotype was unstable, suggesting a phase variation. Transcription profiling revealed that expression of the agr locus and many extracellular virulence factors was repressed in the nonhemolytic variant. Expression of the agr-activating gene, sarU, was also repressed in the nonhemolytic variant, suggesting one potential regulatory pathway responsible for the Agr-deficient phenotype. We suggest that the development of these variants in biofilms may have important clinical implications.

scholarly journals Detection of the agr System and Resistance to Antimicrobials in Biofilm-Producing S. epidermidis

Molecules ◽  
2020 ◽  
Vol 25 (23) ◽  
pp. 5715
Author(s):  
Valéria Cataneli Pereira ◽  
Luiza Pinheiro-Hubinger ◽  
Adilson de Oliveira ◽  
Danilo Flávio Moraes Riboli ◽  
Katheryne Benini Martins ◽  
...  
Keyword(s):  
Virulence Factors ◽  
Antimicrobial Agents ◽  
University Hospital ◽  
Accessory Gene ◽  
Accessory Gene Regulator ◽  
Oxacillin Resistance ◽  
Major Cluster ◽  
Polymerase Chain ◽  
Operon Expression

The ability of Staphylococcus epidermidis to produce virulence factors, such as biofilm, added to its increased resistance to antimicrobials can cause infections that are difficult to treat. Many staphylococcal virulence factors are under the control of the accessory gene regulator (agr). The objective of this study was to establish the agr locus and susceptibility of biofilm-producing S. epidermidis specimens to antimicrobial agents, through PCR reactions, reverse transcription polymerase chain reaction (RT-PCR), and the determination of minimum inhibitory concentration (MIC), and to analyze the clonal profile of 300 strains isolated from blood culture specimens from inpatients at a University Hospital in Brazil, over a 20-year period by pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) techniques. The ica operon expression was shown in 83.6% strains, bhp gene in 11.5%, and aap gene in 32.8%. Oxacillin resistance was detected in 90.1%, while 4.9% showed tigecycline resistance, and intermediate resistance to quinupristin/dalfopristin was identified in 0.4%. Clonal profile determination showed 11 clusters, with the ST2 type determined as the major cluster. The S. epidermidis biofilm producer demonstrated a predominance of agr I locus, oxacillin resistance, and SCCmec III as well as the potential dissemination of pathogenic clones in hospital settings over long periods.

scholarly journals Quorum Sensing and Toxin Production in Staphylococcus aureus Osteomyelitis: Pathogenesis and Paradox

Toxins ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 516
Author(s):  
Casey E. Butrico ◽  
James E. Cassat
Keyword(s):  
Staphylococcus Aureus ◽  
Quorum Sensing ◽  
Toxin Production ◽  
High Morbidity ◽  
Invasive Infection ◽  
Accessory Gene ◽  
Accessory Gene Regulator ◽  
Production Factors ◽  
Regulatory Systems ◽  
Skeletal Homeostasis

Staphylococcus aureus is a Gram-positive pathogen capable of infecting nearly every vertebrate organ. Among these tissues, invasive infection of bone (osteomyelitis) is particularly common and induces high morbidity. Treatment of osteomyelitis is notoriously difficult and often requires debridement of diseased bone in conjunction with prolonged antibiotic treatment to resolve infection. During osteomyelitis, S. aureus forms characteristic multicellular microcolonies in distinct niches within bone. Virulence and metabolic responses within these multicellular microcolonies are coordinated, in part, by quorum sensing via the accessory gene regulator (agr) locus, which allows staphylococcal populations to produce toxins and adapt in response to bacterial density. During osteomyelitis, the Agr system significantly contributes to dysregulation of skeletal homeostasis and disease severity but may also paradoxically inhibit persistence in the host. Moreover, the Agr system is subject to complex crosstalk with other S. aureus regulatory systems, including SaeRS and SrrAB, which can significantly impact the progression of osteomyelitis. The objective of this review is to highlight Agr regulation, its implications on toxin production, factors that affect Agr activation, and the potential paradoxical influences of Agr regulation on disease progression during osteomyelitis.

scholarly journals Identification and characterization of msa (SA1233), a gene involved in expression of SarA and several virulence factors in Staphylococcus aureus

Microbiology ◽  
2006 ◽  
Vol 152 (9) ◽  
pp. 2559-2572 ◽  
Author(s):  
Karthik Sambanthamoorthy ◽  
Mark S. Smeltzer ◽  
Mohamed O. Elasri
Keyword(s):  
Staphylococcus Aureus ◽  
Virulence Factors ◽  
Protein A ◽  
Laboratory Strain ◽  
Reporter System ◽  
Accessory Gene ◽  
Accessory Gene Regulator ◽  
Genes Encoding ◽  
Membrane Spanning ◽  
The Impact

The staphylococcal accessory regulator (sarA) plays a central role in the regulation of virulence in Staphylococcus aureus. To date, studies involving sarA have focused on its activity as a global regulator that modulates transcription of a wide variety of genes (>100) and its role in virulence. However, there is also evidence to suggest the existence of accessory elements that modulate SarA production and/or function. A reporter system was developed to identify such elements, and a new gene, msa (SA1233), mutation of which results in reduced expression of SarA, was identified and characterized. Additionally, it was shown that mutation of msa resulted in altered transcription of the accessory gene regulator (agr) and the genes encoding several virulence factors including alpha toxin (hla) and protein A (spa). However, the impact of mutating msa was different in the laboratory strain RN6390 and the clinical isolate UAMS-1. For instance, mutation of msa caused a decrease in spa and hla transcription in RN6390 but had a different effect in UAMS-1. The strain-dependent effects of the msa mutation were similar to those observed previously, which suggests that msa may modulate the production of specific virulence factors through its impact on sarA. Interestingly, sequence analysis of Msa suggests that it is a putative membrane protein with three membrane-spanning regions, indicating that Msa might interact with the environment. The findings show that msa is involved in the expression of SarA and several virulence factors.

scholarly journals Repression of the Staphylococcus aureus Accessory Gene Regulator in Serum and In Vivo

2002 ◽  
Vol 184 (4) ◽  
pp. 1095-1101 ◽  
Author(s):  
Jeremy M. Yarwood ◽  
John K. McCormick ◽  
Michael L. Paustian ◽  
Vivek Kapur ◽  
Patrick M. Schlievert
Keyword(s):  
Staphylococcus Aureus ◽  
Virulence Factors ◽  
Dna Microarrays ◽  
Expression Profiles ◽  
Rabbit Serum ◽  
Accessory Gene ◽  
Experimental Conditions ◽  
Accessory Gene Regulator

ABSTRACT Subgenomic DNA microarrays were employed to evaluate the expression of the accessory gene regulator (agr locus) as well as multiple virulence-associated genes in Staphylococcus aureus. Gene expression was examined during growth of S. aureus in vitro in standard laboratory medium and rabbit serum and in vivo in subcutaneous chambers implanted in either nonimmune rabbits or rabbits immunized with staphylococcal enterotoxin B. Expression of RNAIII, the effector molecule of the agr locus, was dramatically repressed in serum and in vivo, despite the increased expression of secreted virulence factors sufficient to cause toxic shock syndrome (TSS) in the animals. Statistical analysis and clustering of virulence genes based on their expression profiles in the various experimental conditions demonstrated no positive correlation between the expression of agr and any staphylococcal virulence factors examined. Disruption of the agr locus had only a minimal effect on the expression in vivo of the virulence factors examined. An effect of immunization on the expression of agr and virulence factors was also observed. These results suggest that agr activation is not necessary for development of staphylococcal TSS and that regulatory circuits responding to the in vivo environment override agr activity.

scholarly journals Accessory Gene Regulator-1 Locus Is Essential for Virulence and Pathogenesis ofClostridium difficile

mBio ◽  
2016 ◽  
Vol 7 (4) ◽  
Author(s):  
Charles Darkoh ◽  
Chioma Odo ◽  
Herbert L. DuPont
Keyword(s):  
Health Care ◽  
Therapeutic Target ◽  
Treatment Options ◽  
Toxin Production ◽  
The United States ◽  
Multidrug Resistant ◽  
Accessory Gene ◽  
Ofclostridium Difficile ◽  
Accessory Gene Regulator ◽  
Toxin Regulation

ABSTRACTClostridium difficileinfection (CDI) is responsible for most of the definable cases of antibiotic- and hospital-associated diarrhea worldwide and is a frequent cause of morbidity and mortality in older patients.C. difficile, a multidrug-resistant anaerobic pathogen, causes disease by producing toxins A and B, which are controlled by an accessory gene regulator (Agr) quorum signaling system. SomeC. difficilestrains encode two Agr loci in their genomes, designatedagr1andagr2. Theagr1locus is present in all of theC. difficilestrains sequenced to date, whereas theagr2locus is present in a few strains. The functional roles ofagr1andagr2inC. difficiletoxin regulation and pathogenesis were unknown until now. Using allelic exchange, we deleted components of bothagrloci and examined the mutants for toxin production and virulence. The results showed that theagr1mutant cannot produce toxins A and B; toxin production can be restored by complementation with wild-typeagr1. Furthermore, theagr1mutant is able to colonize but unable to cause disease in a murine CDI model. These findings have profound implications for CDI treatment because we have uncovered a promising therapeutic target for the development of nonantibiotic drugs to treat this life-threatening emerging pathogen by targeting the toxins directly responsible for disease.IMPORTANCEWithin the last decade, the number of cases ofC. difficileinfections has been increasing exponentially in the United States, resulting in about 4.8 billion U.S. dollars in health care costs annually. As a multidrug-resistant, spore-forming, anaerobic pathogen,C. difficileoverpopulates the colon after the gut microbiota has been altered by antibiotic therapy. With increasing resistance to antibiotic treatment ofC. difficileinfections, patients are experiencing higher costs of health care and a lower quality of life as treatment options decrease. During infection,C. difficileproduces toxins A and B, which directly cause disease. As a result, the toxins have become promising nonantibiotic treatment targets. Here, we have identified a pathway responsible for activating the production of the toxins. This important finding opens up a unique therapeutic target for the development of a novel nonantibiotic therapy forC. difficileinfections.

scholarly journals Significant Variability exists in the Toxicity of Global Methicillin-resistant Staphylococcus aureus Lineages.

2021 ◽  
Author(s):  
Maisem Laabei ◽  
Sharon Peacock ◽  
Beth Blane ◽  
Sarah Louise Baines ◽  
Timothy P. Stinear ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Healthcare Setting ◽  
Toxin Production ◽  
Health Concern ◽  
Accessory Gene ◽  
Toxic Activity ◽  
Methicillin Resistant ◽  
Accessory Gene Regulator ◽  
Toxin Regulation ◽  
Reduced Toxicity

Staphylococcus aureus is a major human pathogen where the emergence of antibiotic resistant lineages, such as methicillin-resistant S. aureus (MRSA), is a major health concern. While some MRSA lineages are restricted to the healthcare setting, the epidemiology of MRSA is changing globally, with the rise of specific lineages causing disease in healthy people in the community. In the past two decades, community-associated MRSA (CA-MRSA) has emerged as a clinically important and virulent pathogen associated with serious skin and soft-tissue infections (SSTI). These infections are primarily toxin driven, leading to the suggestion that hyper-virulent lineages/multi-locus sequence types (STs) exist. To examine this, we compared the toxic activity of 475 MRSA isolates representing five major MRSA STs (ST22, ST93, ST8, ST239 and ST36) by employing a monocyte-macrophage THP-1 cell line as a surrogate for measuring gross cytotoxicity. We demonstrate that while certain MRSA STs contain highly toxic isolates, there is such variability within lineages to suggest that this aspect of virulence should not be inferred from the genotype of any given isolate. Furthermore, by interrogating the accessory gene regulator (Agr) sequences in this collection we identified several Agr mutations that were associated with reduced toxicity. Interestingly, the majority of isolates that were attenuated in toxin production contained no mutations in the agr locus, indicating a role of other undefined genes in S. aureus toxin regulation.

Sign in / Sign up

Export Citation Format

Share Document