The Pathology of Diphtheria

Hadfield, Ted L.; McEvoy, Peter; Polotsky, Yury; Tzinserling, Vsevolod A.; Yakovlev, A. A.

doi:10.1086/315551

Cited by 230 publications

(159 citation statements)

References 13 publications

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“…diphtheriae is the classical aetiological agent of diphtheria (Hadfield et al, 2000;Burkovski, 2013a, b), a localized toxaemic infection of respiratory tract that can be fatal. Moreover, it can cause skin ulcers (cutaneous diphtheria) as well as systemic infections such as endocarditis, meningitis, pneumonia and others (Murphy, 1996;Burkovski, 2013b).…”

Section: Introductionmentioning

confidence: 99%

Characterization of DIP0733, a multi-functional virulence factor of Corynebacterium diphtheriae

et al. 2015

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Corynebacterium diphtheriae is typically recognized as an extracellular pathogen. However, a number of studies revealed its ability to invade epithelial cells, indicating a more complex pathogen-host interaction. The molecular mechanisms controlling and facilitating internalization of Cor. diphtheriae are poorly understood. In this study, we investigated the role of DIP0733 as virulence factor to elucidate how it contributes to the process of pathogen-host cell interaction. Based on in vitro experiments, it was suggested recently that the DIP0733 protein might be involved in adhesion, invasion of epithelial cells and induction of apoptosis. A corresponding Cor. diphtheriae mutant strain generated in this study was attenuated in its ability to colonize and kill the host in a Caenorhabditis elegans infection model system. Furthermore, the mutant showed an altered adhesion pattern and a drastically reduced ability to adhere and invade epithelial cells. Subsequent experiments showed an influence of DIP0733 on binding of Cor. diphtheriae to extracellular matrix proteins such as collagen and fibronectin. Furthermore, based on its fibrinogen-binding activity, DIP0733 may play a role in avoiding recognition of Cor. diphtheriae by the immune system. In summary, our findings support the idea that DIP0733 is a multi-functional virulence factor of Cor. diphtheriae.

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Section: Introductionmentioning

confidence: 99%

Characterization of DIP0733, a multi-functional virulence factor of Corynebacterium diphtheriae

et al. 2015

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“…Although diphtheria has now been virtually eliminated in the industrialized world, rare outbreaks still occur worldwide (1,2). Corynebacterium diphtheriae was shown to be the causative agent of diphtheria by Loeffler in 1885 (3), and Roux and Yersin showed that an extracellular toxin, diphtheria toxin (DT) secreted by C. diphtheriae is responsible for toxicity (4).…”

mentioning

confidence: 99%

Structural basis for lack of toxicity of the diphtheria toxin mutant CRM197

Malito

Bursulaya

Chen

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

120

107

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CRM197 is an enzymatically inactive and nontoxic form of diphtheria toxin that contains a single amino acid substitution (G52E). Being naturally nontoxic, CRM197 is an ideal carrier protein for conjugate vaccines against encapsulated bacteria and is currently used to vaccinate children globally against Haemophilus influenzae, pneumococcus, and meningococcus. To understand the molecular basis for lack of toxicity in CRM197, we determined the crystal structures of the full-length nucleotide-free CRM197 and of CRM197 in complex with the NAD hydrolysis product nicotinamide (NCA), both at 2.0-Å resolution. The structures show for the first time that the overall fold of CRM197 and DT are nearly identical and that the striking functional difference between the two proteins can be explained by a flexible active-site loop that covers the NAD binding pocket. We present the molecular basis for the increased flexibility of the active-site loop in CRM197 as unveiled by molecular dynamics simulations. These structural insights, combined with surface plasmon resonance, NAD hydrolysis, and differential scanning fluorimetry data, contribute to a comprehensive characterization of the vaccine carrier protein, CRM197.

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“…When Corynebacterium diphtheriae infects humans, it generally has an incubation period of 2 to 5 days [129]. It typically infects anterior nasal, tonsillar and pharyngeal, laryngeal, cutaneous, ocular and genital areas, which means that it can grow in any mucous membrane and in the skin [52,82]. As well as destroying local cells at infection sites, the diphtheria toxin can also enter the bloodstream and reach out to organ cells that have its receptor, typically heart and nerve cells.…”

Section: How Corynebacterium Diphtheriae Causes Illnessmentioning

confidence: 99%

The Evolution and Value of Diphtheria Vaccine

Bae¹

2011

KSBB Journal

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1) This review article provides an overview of the evolution of diphtheria vaccine, its value and its future. Diphtheria is an infectious illness caused by diphtheria toxin produced by pathogenic strains of Corynebacterium diphtheriae. It is characterized by a sore throat with membrane formation due to local tissue necrosis, which can lead to fatal airway obstruction; neural and cardiac damage are other common complications. Diphtheria vaccine was first brought to market in the 1920s, following the discovery that diphtheria toxin can be detoxified using formalin. However, conventional formalin-inactivated toxoid vaccines have some fundamental limitations. Innovative technologies and approaches with the potential to overcome these limitations are discussed in this paper. These include genetic inactivation of diphtheria toxoid, innovative vaccine delivery systems, new adjuvants (both TLRindependent and TLR-dependent adjuvants), and heat-and freeze-stable agents, as well as novel platforms for producing improved conventional vaccine, DNA vaccine, transcutaneous (microneedle-mediated) vaccine, oral vaccine and edible vaccine expressed in transgenic plants. These innovations target improvements in vaccine quality (efficacy, safety, stability and consistency), ease of use and/or thermal stability. Their successful development and use should help to increase global diphtheria vaccine coverage.

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The Pathology of Diphtheria

Cited by 230 publications

References 13 publications

Characterization of DIP0733, a multi-functional virulence factor of Corynebacterium diphtheriae

Characterization of DIP0733, a multi-functional virulence factor of Corynebacterium diphtheriae

Structural basis for lack of toxicity of the diphtheria toxin mutant CRM197

The Evolution and Value of Diphtheria Vaccine

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