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Concept: Corynebacterium diphtheriae

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Diphtheria remains a major public health concern with multiple recent outbreaks around the world. Moreover, invasive non-toxigenic strains have emerged globally causing severe infections. A diphtheria epidemic in the former Soviet Union in the 1990s resulted in ~5000 deaths. In this study, we analysed the genome sequences of a collection of 93 C. diphtheriae strains collected during and after this outbreak (1996 - 2014) in a former Soviet State, Belarus to understand the evolutionary dynamics and virulence capacities of these strains.

Concepts: Epidemiology, Infectious disease, Russia, Soviet Union, Diphtheria, Corynebacterium, Post-Soviet states, Corynebacterium diphtheriae

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Non-toxigenic Corynebacterium diphtheriae strains are emerging as a major cause of severe pharyngitis and tonsillitis as well as invasive diseases such as endocarditis, septic arthritis, splenic abscesses and osteomyelitis. C. diphtheriae strains have been reported to vary in their ability to adhere and invade different cell lines. To identify the genetic basis of variation in the degrees of pathogenicity, we sequenced the genomes of four strains of C. diphtheriae (ISS 3319, ISS 4060, ISS 4746 and ISS 4749) that are well characterised in terms of their ability to adhere and invade mammalian cells.

Concepts: DNA, Gene, Genetics, Cell, Inflammations, Diphtheria, Corynebacterium, Corynebacterium diphtheriae

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Diphtheria is an acute, highly infectious, vaccine-preventable and previously endemic disease whose etiologic agent is Corynebacterium diphtheriae. Diphtheria may manifest as an upper respiratory tract infection, a cutaneous infection or as an asymptomatic carrier state. The most common sites of infection are the pharynx and the tonsils, with common clinical manifestations that include sore throat, malaise, cervical lymphadenopathy and low-grade fever. Absorption and dissemination of C. diphtheriae from the respiratory tract can cause disseminated infection and may lead to cardiac or neurological toxicity. The cornerstone of treatment for diphtheria is diphtheria antitoxin. Early treatment is critical as the degree of protection is inversely proportional to the duration of the illness before its administration. Routine childhood vaccination virtually eliminated diphtheria in most industrialised countries. However, in the pre-vaccination era, diphtheria was the most common infectious cause of death in Australia. A case of diphtheria in Brisbane in April 2011 and two recent positive cultures in regional Victoria underscore the need for heightened awareness of C. diphtheriae as an important pathogen. In order to prevent the re-emergence of diphtheria in Australia, public health measures are required to increase immunity in early school leavers and the adult population, and to ensure that travellers to endemic regions are fully immunised. Health policy-makers and clinicians alike should not underestimate the importance of primary vaccination and booster vaccination against diphtheria among healthy adults and travellers.

Concepts: Epidemiology, Infectious disease, Malaria, Respiratory system, Upper respiratory tract, Upper respiratory tract infection, Diphtheria, Corynebacterium diphtheriae

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Infection with Corynebacterium diphtheriae persists in Haiti. Twenty-six children with clinically severe respiratory diphtheria presented to a hospital in northern Haiti during a 3-year period beginning in early 2015. The mortality rate was 50%. Partial or absent vaccinations as well as delayed and limited care contributed to mortality. This cohort offer insights into the multiple challenges involved in preventing and caring for children with diphtheria in resource-limited settings.

Concepts: Mortality rate, Actuarial science, Diphtheria, Corynebacterium diphtheriae

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Corynebacterium ulcerans, an emerging pathogen related to C. diphtheriae and C. pseudotuberculosis, is able to cause disease in both human and animal hosts. C. ulcerans may harbor acquired virulence factors such as dermonecrotic exotoxin phospholipase D (PLD) and the prophage-encoded diphtheria toxin (DT). Infections typically occur in persons reporting close contact with animals. In pets, C. ulcerans has been isolated from both asymptomatic carriers and clinically affected dogs and cats. We describe the isolation and characterization of C. ulcerans strains from 2 pet dogs with ulcerative lesions in Italy. The 2 isolates tested negative for both DT genes, but were PLD-producers and belonged to sequence types (STs) 325 and 339. These 2 cases highlight that C. ulcerans cutaneous infections might be underestimated in pets, given that many veterinary laboratories do not routinely consider and/or identify Corynebacterium species from cutaneous samples. Early detection and molecular typing of C. ulcerans is essential in order to implement effective treatment and to prevent diffusion and possible zoonotic transmission of certain STs.

Concepts: Disease, Dog, Pet, Virulence, Zoonosis, Diphtheria, Corynebacterium, Corynebacterium diphtheriae

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CRM197, a single amino acid mutant of diphtheria toxoid, is a commonly used carrier protein in commercial polysaccharide-protein conjugate vaccines. In this study, CRM197proteins from three different expression systems and five different manufacturers were obtained for an analytical comparability assessment using a wide variety of physicochemical and in vitro antigenic binding assays. A comprehensive analysis of the five CRM197molecules demonstrate that recombinant CRM197’s expressed in heterologous systems (E. coli and Pseudomonas fluorescens) are overall highly similar (if not better in some cases) to those expressed in the traditional system (Corynebacterium diphtheriae) in terms of primary sequence/post translational modifications, higher-order structural integrity, apparent solubility, physical stability profile (vs. pH and temperature) and in vitro antigenicity. These results are an encouraging step to demonstrate that recombinant CRM197expressed in alternative sources have the potential to replace CRM197expressed in C. diphtheriae as a source of immunogenic carrier protein for lower-cost polysaccharide conjugate vaccines. The physicochemical assays established in this work to monitor the key structural attributes of CRM197should also prove useful as complementary characterization methods (to routine quality control assays) to support future process and formulation development of lower-cost CRM197carrier proteins for use in various conjugate vaccines.

Concepts: Protein, Gene, Amino acid, Acid, Escherichia coli, Antigen, Diphtheria, Corynebacterium diphtheriae

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Corynebacterium diphtheriae is a re-emerging pathogen in Europe causing invasive infections in vaccinated persons and classical diphtheria in unvaccinated persons. In the presented study we analysed genetic changes in C. diphtheriae isolates collected in Poland from the period before the introduction of the mass anti-diphtheria vaccination to the present time when over 98% of the population is vaccinated.

Concepts: Immune system, Present, Time, Diphtheria, Corynebacterium diphtheriae

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Corynebacterium diphtheriae , a Gram-positive, aerobic bacterium, is the causative agent of diphtheria and cutaneous infections. While mechanisms required for heme iron acquisition are well known inC. diphtheriae, systems involved in the acquisition of other metals such as zinc and manganese remain poorly characterized. In this study, we identified a genetic region that encodes an ABC-type transporter (iutBCD) flanked by two genes (iutAandiutE) encoding putative substrate binding proteins of the cluster 9 family, a related group of transporters primarily associated with the import of Mn and Zn. We showed that IutA and IutE are both membrane proteins with comparable Mn and Zn binding ability. We demonstrated that theiutABCDgenes are co-transcribed and repressed in response to iron by the iron-responsive repressor DtxR. Transcription ofiutEwas positively regulated in response to iron availability in a DtxR-dependent manner, and repressed in response to Zn by the Zn-dependent repressor Zur. Electrophoretic mobility shift assays showed that DtxR does not bind to theiutEupstream region, which indicates that DtxR regulation ofiutEis indirect and that other regulatory factors controlled by DtxR are likely responsible for the iron-responsive regulation. Analysis of theiutEpromoter region identified a 50-bp sequence at the 3' end of theiutDgene that is required for the DtxR-dependent and iron-responsive activation of theiutEgene. These findings indicate that transcription ofiutEis controlled by a complex mechanism that involves multiple regulatory factors whose activity is impacted by both Zn and Fe.IMPORTANCEVaccination against diphtheria prevents toxin-related symptoms, but does not inhibit bacterial colonization of the human host by the bacterium. Thus,Corynebacterium diphtheriaeremains an important human pathogen that poses a significant health risk to unvaccinated individuals. The ability to acquire iron, zinc, and manganese is critical to the pathogenesis of many disease-causing organisms. Here, we describe a gene cluster inC. diphtheriaethat encodes a metal importer that is homologous to broadly distributed metal transport systems, some with important roles in virulence in other bacterial pathogens. Two metal-binding components of the gene cluster encode surface exposed proteins, and studies of such proteins may guide the development of second generation vaccines forC. diphtheriae.

Concepts: DNA, Gene, Gene expression, Bacteria, Pathogen, Metal, Regulation, Corynebacterium diphtheriae

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Corynebacterium ulcerans infection was recently recognized as a zoonosis. We present 2 cases of severe pneumonia complicated by diffuse pseudomembrane formation on the bronchus caused by C. ulcerans-producing diphtheria toxin. Our purpose is to alert medical professionals to the virulence of Corynebacterium species other than C. diphtheriae.

Concepts: Infectious disease, Bacteria, Toxin, Diphtheria, Corynebacterium, Corynebacterium diphtheriae

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Toxigenic strains of Corynebacterium diphtheriae cause the majority of respiratory diphtheria cases. However, nontoxigenic strains of C. diphtheriae can also cause diseases, and have become increasingly common. Infection that is limited to the anterior nares (nasal diphtheria) is a well-described but rare condition, even for toxigenic C. diphtheriae. We report a case involving chronic carriage of nasal diphtheria caused by nontoxigenic C. diphtheriae, as well as a review of other reported nontoxigenic C. diphtheriae cases in Japan. Mild or asymptomatic nasal diphtheria involving nontoxigenic strains, which can be the source of transmission, may be underrecognized. Our case highlights the importance of awareness regarding nontoxigenic diphtheria among clinicians, especially in the era of improved diphtheria vaccination coverage.

Concepts: Infectious disease, Causality, Report, Case, Nose, Source, Diphtheria, Corynebacterium diphtheriae