<i>Staphylococcus aureus</i>toxin antibodies: Good companions of antibiotics and vaccines

Bagnoli, Fábio

doi:10.1080/21505594.2017.1295205

Cited by 11 publications

(10 citation statements)

References 27 publications

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“…Among antigens that have been proposed as targets for vaccine development, the alpha haemolysin toxin gene hla [ 147 , 156 , 157 ] and the genes coding for capsular biosynthesis cap5 and cap8 [ 150 , 151 ] are highly prevalent in our cohort (91.9% and 97.8% of the isolates respectively). Nevertheless, these genes showed a larger degree of variability compared to the others we considered, which may explain the poor results obtained in clinical trials [ 147 , 150 , 151 , 156 , 157 ]. Other genes that code for proteins used alone or in combination in vaccine formulations, such as the virulence determinant SpA [ 158 ] and the fibronectin-binding protein ClfA [ 159 – 161 ], are present in most of our strain collection.…”

Section: Resultsmentioning

confidence: 99%

Whole-genome epidemiology, characterisation, and phylogenetic reconstruction of Staphylococcus aureus strains in a paediatric hospital

et al. 2018

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BackgroundStaphylococcus aureus is an opportunistic pathogen and a leading cause of nosocomial infections. It can acquire resistance to all the antibiotics that entered the clinics to date, and the World Health Organization defined it as a high-priority pathogen for research and development of new antibiotics. A deeper understanding of the genetic variability of S. aureus in clinical settings would lead to a better comprehension of its pathogenic potential and improved strategies to contrast its virulence and resistance. However, the number of comprehensive studies addressing clinical cohorts of S. aureus infections by simultaneously looking at the epidemiology, phylogenetic reconstruction, genomic characterisation, and transmission pathways of infective clones is currently low, thus limiting global surveillance and epidemiological monitoring.MethodsWe applied whole-genome shotgun sequencing (WGS) to 184 S. aureus isolates from 135 patients treated in different operative units of an Italian paediatric hospital over a timespan of 3 years, including both methicillin-resistant S. aureus (MRSA) and methicillin-sensitive S. aureus (MSSA) from different infection types. We typed known and unknown clones from their genomes by multilocus sequence typing (MLST), Staphylococcal Cassette Chromosome mec (SCCmec), Staphylococcal protein A gene (spa), and Panton-Valentine Leukocidin (PVL), and we inferred their whole-genome phylogeny. We explored the prevalence of virulence and antibiotic resistance genes in our cohort, and the conservation of genes encoding vaccine candidates. We also performed a timed phylogenetic investigation for a potential outbreak of a newly emerging nosocomial clone.ResultsThe phylogeny of the 135 single-patient S. aureus isolates showed a high level of diversity, including 80 different lineages, and co-presence of local, global, livestock-associated, and hypervirulent clones. Five of these clones do not have representative genomes in public databases. Variability in the epidemiology is mirrored by variability in the SCCmec cassettes, with some novel variants of the type IV cassette carrying extra antibiotic resistances. Virulence and resistance genes were unevenly distributed across different clones and infection types, with highly resistant and lowly virulent clones showing strong association with chronic diseases, and highly virulent strains only reported in acute infections. Antigens included in vaccine formulations undergoing clinical trials were conserved at different levels in our cohort, with only a few highly prevalent genes fully conserved, potentially explaining the difficulty of developing a vaccine against S. aureus. We also found a recently diverged ST1-SCCmecIV-t127 PVL− clone suspected to be hospital-specific, but time-resolved integrative phylogenetic analysis refuted this hypothesis and suggested that this quickly emerging lineage was acquired independently by patients.ConclusionsWhole genome sequencing allowed us to study the epidemiology and genomic repertoire of S. aureus in a clin...

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Section: Resultsmentioning

confidence: 99%

Whole-genome epidemiology, characterisation, and phylogenetic reconstruction of Staphylococcus aureus strains in a paediatric hospital

et al. 2018

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“…Combined anti-toxin/antibiotic therapies or indirect approaches targeting the agr-QS system that governs S. aureus virulence might be more effective at blocking the progressions of staphylococcal diseases [9][10][11][12]. Recently, RNAIII-inhibiting heptapeptide (RIP) and sarvirin were reported to disrupt the Agr-QS system and reduce S. aureus virulence [5].…”

Section: Anti-virulence Therapies and Natural Productsmentioning

confidence: 99%

“…aureus rapidly acquires antibiotic resistance, and the emergence of multidrug-resistant strains is an enormous burden. It has been reported the annual death toll due to antibiotic-resistant infections has reached 10 million, and that in 2050 it will exceed the number of deaths attributed to cancer [9]. Thus, the appropriate uses of antibiotics and alternative therapeutic approaches have become necessities.…”

Section: Introductionmentioning

confidence: 99%

“…Recently, anti-toxin antibodies that neutralize individual toxins have been engineered and shown to be effective at preventing or treating staphylococcal diseases [10][11][12]. Even a combined anti-toxin/antibiotic therapy has been reported to be effective at blocking the progressions of staphylococcal diseases [9]. However, neutralization of a single toxin may not adequately safeguard the host from S. aureus infection.…”

Section: Introductionmentioning

confidence: 99%

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Staphylococcus aureus Toxins: From Their Pathogenic Roles to Anti-virulence Therapy Using Natural Products

Kim

2019

Biotechnol Bioproc E

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Staphylococcus aureus (S. aureus) produces a wide variety of toxins that cause various diseases in humans. S. aureus toxins are divided into three categories; (i) superantigens (SAgs) that interfere with receptor function and cause toxic shock syndrome (TSS) or staphylococcal food poisoning (SFP), (ii) exfoliative toxins (ETs) that destroy epidermal barrier functions and cause staphylococcal scalded skin syndrome (SSSS), and (iii) cytotoxins that cause cell lysis. Recently, anti-toxin neutralizing agents have been engineered and proven to be effective in preventing or treating staphylococcal diseases. However, neutralization of a single toxin may not sufficiently protect the host from S. aureus infection. Biofilm formation and the pathogenesis of S. aureus are closely associated with accessory gene regulator-quorum sensing (agr-QS) system that controls the expressions of many virulence factors including exotoxins. In addition to anti-toxin antibodies, indirect approaches involving targeting of the agr-QS system are considered a novel means of inhibiting the virulence of S. aureus and controlling various diseases caused by the pathogen. This review summarizes basic concepts of the pathogenic roles of S. aureus toxins, the molecular features of the agr-QS system, and of natural product-based anti-virulence therapies that target virulence, rather than growth.

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“…Prominent examples for toxin-based vaccination strategies are vaccines targeting C. difficile toxins tcdA and tcdB to prevent manifestation of C. difficile infection (CDI). Additionally, some vaccine prototypes (and monoclonal antibodies) are targeting S. aureus toxins such as alpha toxin (hemolysin A), staphylococcal eneterotoxin B (SEB) and other secreted toxins such as leukocidins [reviewed in ( 4 , 5 , 40 – 42 )]. The general assumption is that raising the level of neutralizing antibodies against toxins prevents invasive disease and lowers disease severity.…”

Section: The Immunological Mechanism Of Actionmentioning

confidence: 99%

Challenges for Clinical Development of Vaccines for Prevention of Hospital-Acquired Bacterial Infections

Bekeredjian‐Ding

2020

Front. Immunol.

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Increasing antibiotic resistance in bacteria causing endogenous infections has entailed a need for innovative approaches to therapy and prophylaxis of these infections and raised a new interest in vaccines for prevention of colonization and infection by typically antibiotic resistant pathogens. Nevertheless, there has been a long history of failures in late stage clinical development of this type of vaccines, which remains not fully understood. This article provides an overview on present and past vaccine developments targeting nosocomial bacterial pathogens; it further highlights the specific challenges associated with demonstrating clinical efficacy of these vaccines and the facts to be considered in future study designs. Notably, these vaccines are mainly applied to subjects with preexistent immunity to the target pathogen, transient or chronic immunosuppression and ill-defined microbiome status. Unpredictable attack rates and changing epidemiology as well as highly variable genetic and immunological strain characteristics complicate the development. In views of the clinical need, rethinking of the study designs and expectations seems warranted: first of all, vaccine development needs to be footed on a clear rationale for choosing the immunological mechanism of action and the optimal time point for vaccination, e.g., (1) prevention (or reduction) of colonization vs. prevention of infection and (2) boosting of a preexistent immune response vs. altering the quality of the immune response. Furthermore, there are different, probably redundant, immunological and microbiological defense mechanisms that provide protection from infection. Their interplay is not well-understood but as a consequence their effect might superimpose vaccine-mediated resolution of infection and lead to failure to demonstrate efficacy. This implies that improved characterization of patient subpopulations within the trial population should be obtained by pro-and retrospective analyses of trial data on subject level. Statistical and systems biology approaches could help to define immune and microbiological biomarkers that discern populations that benefit from vaccination from those where vaccines might not be effective.

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Staphylococcus aureustoxin antibodies: Good companions of antibiotics and vaccines

Cited by 11 publications

References 27 publications

Whole-genome epidemiology, characterisation, and phylogenetic reconstruction of Staphylococcus aureus strains in a paediatric hospital

Whole-genome epidemiology, characterisation, and phylogenetic reconstruction of Staphylococcus aureus strains in a paediatric hospital

Staphylococcus aureus Toxins: From Their Pathogenic Roles to Anti-virulence Therapy Using Natural Products

Challenges for Clinical Development of Vaccines for Prevention of Hospital-Acquired Bacterial Infections

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