PATHOGENICITY OF CORYNEBACTERIUM DIPHTHERIA
Diphtheria toxin is a protein produced by pathogenic Corynebacterium diphtheriae strains.
Toxigenic strains lead to the disease by secreting and increasing number of diphtheria exotoxin in either nasopharyngeal or skin lesions.
This can spread from person to person via respiratory droplets such as from sneezing or coughing (Murphy, 2020).
This exotoxin produced by Corynebacterium deactivates eukaryotic translation elongation factor 2 by binding to it, which then stops the translation in the protein synthesis, as a result, it leads to the eukaryotic cells to die. Furthermore, the waste products and proteins produced by toxin can cause pseudomembrane to attach with nasal tissues, larynx, pharynx, and tonsils which can block breathing.
In addition, if exotoxin increases and starts to spread in the bloodstream then it can damage remote organs, for example, kidneys, heart, and liver which can also lead to death (Wenzel et al., 2020).
This exotoxin is ‘Y’ shaped, it consists of a single polypeptide chain with 535 amino acids and it has A-B subunits combined by disulfide bridge.
Subunit A-B has 3 structural domains, where each has different biological functions.
The C domain makes up the A subunit, T, and R domains make up the B subunit.
Subunit B consists of:
1. Receptor binding domain, that has the function to recognize specific receptor found on the surface of host cells. This process allows the endocytosis of the toxin.
2. Translocation/transmembrane domain, that enters the endosome when the environment has low pH, and its function is to help transport the catalytic domain into the cytoplasm.
Subunit A consists of:
Catalytic domain, it carries toxic and functions to transport ADP-ribose from cytosolic NAD to the substrate, called elongation factor 2. This process stops cellular proteins from synthesizing as a result it leads to cell apoptosis.
Glutamic acid 148 in the active site of the C domain forms a stable bond with the nicotinamide group which allows ADP ribose to bond and attack diphthamide in EF2 (Leone, 2020).
Exotoxin is coded by tox gene, and it enters by a lysogenic bacteriophage B-phage.
The binding receptor in subunit B binds with the heparin binding epidermal growth factor receptor found on the surface of the host cells such as nerve cell or heart cells. The attachment of the receptor domain to heparin-binding epidermal growth factor and cell membrane proteins CD-9 allows the toxin to enter the cell.
A-B toxin enter the cell by endocytosis, the cell engulfs the toxin in an endosome. This causes the content of vacuole to become acidic leading A-B units to separate.
Unit A enters the cytoplasm of the cell and applies toxic effects, while unit B leaves the cell by exocytosis.
Subunit A transfer's adenine ribose phosphate from NAD to EF-2 known as ADP ribosylation. This disables EF-2 and stops protein synthesis in cells.
Lysogenised toxin synthesis is managed by a chromosomally encode osmolarity d element, diphtheria toxin repressor (DTxR) which is activated when iron concentrations increase, and it can attach to the operator of toxin gene and inhibit toxin formation. Therefore, the virulence of Corynebacterium diphtheriae disease is associated with diphtheria toxin repressor (DtxR) (Diphtheria toxin: The nuts and bolts, 2019).
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