Materiały źródłowe

• #1 Corynebacterium Diphtheriae – Medical Microbiology – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK7971/

  Corynebacterium diphtheriae infects the nasopharynx or skin. Toxigenic strains secrete a potent exotoxin which may cause diphtheria. The diphtheritic lesion is often covered by a pseudomembrane composed of fibrin, bacteria, and inflammatory cells. Diphtheria toxin can be proteolytically cleaved into two fragments: an N-terminal fragment A (catalytic domain), and fragment B (transmembrane and receptor binding domains). Fragment A catalyzes the NAD+-dependent ADP-ribosylation of elongation factor 2, thereby inhibiting protein synthesis in eukaryotic cells. Fragment B binds to the cell surface receptor and facilitates the delivery of fragment A to the cytosol. […] The pathogenesis of diphtheria is based upon two primary determinants: (1) the ability of a given strain of C diphtheriae to colonize in the nasopharyngeal cavity and/or on the skin, and (2) its ability to produce diphtheria toxin. Since those determinants involved in colonization of the host are encoded by the bacteria, and the toxin is encoded by the corynebacteriophage, the molecular basis of virulence in C diphtheriae results from the combined effects of determinants carried on two genomes. Nontoxigenic strains of C diphtheriae are rarely associated with clinical disease; however, they may become highly virulent following lysogenic conversion to toxigenicity.

• #2 Corynebacterium Diphtheriae – Medical Microbiology – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK7971/

  Corynebacterium diphtheriae infects the nasopharynx or skin. Toxigenic strains secrete a potent exotoxin which may cause diphtheria. The diphtheritic lesion is often covered by a pseudomembrane composed of fibrin, bacteria, and inflammatory cells. Diphtheria toxin can be proteolytically cleaved into two fragments: an N-terminal fragment A (catalytic domain), and fragment B (transmembrane and receptor binding domains). Fragment A catalyzes the NAD+-dependent ADP-ribosylation of elongation factor 2, thereby inhibiting protein synthesis in eukaryotic cells. Fragment B binds to the cell surface receptor and facilitates the delivery of fragment A to the cytosol. […] The pathogenesis of diphtheria is based upon two primary determinants: (1) the ability of a given strain of C diphtheriae to colonize in the nasopharyngeal cavity and/or on the skin, and (2) its ability to produce diphtheria toxin. Since those determinants involved in colonization of the host are encoded by the bacteria, and the toxin is encoded by the corynebacteriophage, the molecular basis of virulence in C diphtheriae results from the combined effects of determinants carried on two genomes. Nontoxigenic strains of C diphtheriae are rarely associated with clinical disease; however, they may become highly virulent following lysogenic conversion to toxigenicity.

• #3 Corynebacterium diphtheriae (Klebs-Löffler bacillus)- An Overview

  https://microbenotes.com/corynebacterium-diphtheriae/

  In nature, C diphtheriae occurs in the respiratory tract, in wounds, or on the skin of infected persons or normal carriers. […] It is spread by droplets or by contact to susceptible individuals; the bacilli then grow on mucous membranes or in skin abrasions, and those that are toxigenic start producing toxin. […] Diphtheria toxin is the major virulence factor of C. diphtheria and is a heat-labile, single-chain, three domain polypeptide (62 kDa) that can be lethal in a dose of 0.1 g/kg body weight. […] The tox gene that codes for the exotoxin is introduced into strains of C. diphtheriae by a lysogenic bacteriophage, -phage. […] Two processing steps are necessary for the active gene product to be secreted: (1) proteolytic cleavage of the leader sequence from the Tox protein during secretion from the bacterial cell and (2) cleavage of the toxin molecule into two polypeptides (A and B) that remain attached by a disulfide bond.

• #4 Corynebacterium Diphtheriae – Medical Microbiology – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK7971/

  The structural gene for diphtheria toxin, tox, is carried by a family of closely related corynebacteriophages of which the -phage is the most extensively studied. The regulation of diphtheria tox expression is mediated by an iron-activated repressor, DtxR, which is encoded on the C diphtheriae genome. The expression of tox depends on the physiologic state of C diphtheriae. Under conditions in which iron becomes the growth-rate limiting substrate, iron dissociates from DtxR, the tox gene becomes derepressed, and diphtheria toxin is synthesized and secreted into the culture medium at maximal rates. […] Diphtheria toxin is extraordinarily potent; in sensitive species (e.g., humans, monkeys, rabbits, guinea pigs) as little as 100 to 150 ng/kg of body weight is lethal. Diphtheria toxin is composed of a single polypeptide chain of 535 amino acids. Biochemical genetic and X-ray crystallographic analysis show that the toxin is composed of three structural/functional domains: an N-terminal ADP-ribosyltransferase (catalytic domain); (2) a region which facilitates the delivery of the catalytic domain across the cell membrane (transmembrane domain); and (3) the eukaryotic cell receptor binding domain. Following mild digestion with trypsin and reduction under denaturing conditions, diphtheria toxin may be specifically cleaved in its protease-sensitive loop into two polypeptide fragments (A and B). Fragment A is the N-terminal 21 kDa component of the toxin and contains the catalytic center for the ADP-ribosylation of elongation factor 2 (EF-2) according to the following reaction:

• #5 Diptheria | PPT

  https://www.slideshare.net/slideshow/diptheria-129125486/129125486

  Diphtheria is an infection caused by the bacterium Corynebacterium diphtheriae. […] The pathogenesis of diphtheria is based upon two primary determinants: 1. the ability of a given strain of C diphtheriae to colonize in the nasopharyngeal cavity and/or on the skin 2. its ability to produce diphtheria toxin. […] The structural gene for diphtheria toxin, tox, is carried by a family of closely related corynebacteriophages. […] Diphtheria toxin is extraordinarily potent: as little as 100 to 150 ng/kg of body weight is lethal. […] Intoxication of a single eukaryotic cell by diphtheria toxin can lead to complete irreversible inhibition of protein synthesis (by binding to elongation factor 2, EF-2).

• #6 Diphtheria – Wikipedia

  https://en.wikipedia.org/wiki/Diphtheria

  Diphtheria toxin (DT) is produced only by C. diphtheriae infected with a certain type of bacteriophage. Toxinogenicity is determined by phage conversion (also called lysogenic conversion); i.e., the ability of the bacterium to make DT changes as a consequence of infection by a particular phage. DT is encoded by the tox gene. Strains of corynephage are either tox+ (e.g., corynephage ) or tox (e.g., corynephage ). The tox gene becomes integrated into the bacterial genome. […] The diphtheria toxin precursor is a protein of molecular weight 60 kDa. Certain proteases, such as trypsin, selectively cleave DT to generate two peptide chains, amino-terminal fragment A (DT-A) and carboxyl-terminal fragment B (DT-B), which are held together by a disulfide bond. DT-B is a recognition subunit that gains entry of DT into the host cell by binding to the EGF-like domain of heparin-binding EGF-like growth factor on the cell surface. This signals the cell to internalize the toxin within an endosome via receptor-mediated endocytosis. Inside the endosome, DT is split by a trypsin-like protease into DT-A and DT-B. The acidity of the endosome causes DT-B to create pores in the endosome membrane, thereby catalyzing the release of DT-A into the cytoplasm.

• #7 Corynebacterium Diphtheriae – Medical Microbiology – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK7971/

  The structural gene for diphtheria toxin, tox, is carried by a family of closely related corynebacteriophages of which the -phage is the most extensively studied. The regulation of diphtheria tox expression is mediated by an iron-activated repressor, DtxR, which is encoded on the C diphtheriae genome. The expression of tox depends on the physiologic state of C diphtheriae. Under conditions in which iron becomes the growth-rate limiting substrate, iron dissociates from DtxR, the tox gene becomes derepressed, and diphtheria toxin is synthesized and secreted into the culture medium at maximal rates. […] Diphtheria toxin is extraordinarily potent; in sensitive species (e.g., humans, monkeys, rabbits, guinea pigs) as little as 100 to 150 ng/kg of body weight is lethal. Diphtheria toxin is composed of a single polypeptide chain of 535 amino acids. Biochemical genetic and X-ray crystallographic analysis show that the toxin is composed of three structural/functional domains: an N-terminal ADP-ribosyltransferase (catalytic domain); (2) a region which facilitates the delivery of the catalytic domain across the cell membrane (transmembrane domain); and (3) the eukaryotic cell receptor binding domain. Following mild digestion with trypsin and reduction under denaturing conditions, diphtheria toxin may be specifically cleaved in its protease-sensitive loop into two polypeptide fragments (A and B). Fragment A is the N-terminal 21 kDa component of the toxin and contains the catalytic center for the ADP-ribosylation of elongation factor 2 (EF-2) according to the following reaction:

• #8 Corynebacterium diphtheriae (Klebs-Löffler bacillus)- An Overview

  https://microbenotes.com/corynebacterium-diphtheriae/

  Toxin Fragment A inactivates EF-2 by catalyzing a reaction that yields free nicotinamide plus an inactive adenosine diphosphate-ribose-EF-2 complex (ADP-ribosylation). […] Because the turnover of EF-2 is very slow and approximately only one molecule per ribosome is present in a cell, it has been estimated that one exotoxin molecule can inactivate the entire EF-2 content in a cell, completely terminating host cell protein synthesis. […] It is assumed that the abrupt arrest of protein synthesis is responsible for the necrotizing and neurotoxic effects of diphtheria toxin. […] Toxin synthesis by lysogenized C diptheriae is regulated by a chromosomally encoded element, diphtheria toxin repressor (DTxR) which is activated in the presence of high iron concentrations, and can bind to the toxin gene operator and prevent toxin production. […] Low iron concentration and other factors such as osmolarity, amino acid concentrations and pH, however enhance the production of toxin.

• #9 Corynebacterium Diphtheriae – Medical Microbiology – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK7971/

  The structural gene for diphtheria toxin, tox, is carried by a family of closely related corynebacteriophages of which the -phage is the most extensively studied. The regulation of diphtheria tox expression is mediated by an iron-activated repressor, DtxR, which is encoded on the C diphtheriae genome. The expression of tox depends on the physiologic state of C diphtheriae. Under conditions in which iron becomes the growth-rate limiting substrate, iron dissociates from DtxR, the tox gene becomes derepressed, and diphtheria toxin is synthesized and secreted into the culture medium at maximal rates. […] Diphtheria toxin is extraordinarily potent; in sensitive species (e.g., humans, monkeys, rabbits, guinea pigs) as little as 100 to 150 ng/kg of body weight is lethal. Diphtheria toxin is composed of a single polypeptide chain of 535 amino acids. Biochemical genetic and X-ray crystallographic analysis show that the toxin is composed of three structural/functional domains: an N-terminal ADP-ribosyltransferase (catalytic domain); (2) a region which facilitates the delivery of the catalytic domain across the cell membrane (transmembrane domain); and (3) the eukaryotic cell receptor binding domain. Following mild digestion with trypsin and reduction under denaturing conditions, diphtheria toxin may be specifically cleaved in its protease-sensitive loop into two polypeptide fragments (A and B). Fragment A is the N-terminal 21 kDa component of the toxin and contains the catalytic center for the ADP-ribosylation of elongation factor 2 (EF-2) according to the following reaction:

• #10 Diptheria | PPT

  https://www.slideshare.net/slideshow/diptheria-129125486/129125486

  Diphtheria is an infection caused by the bacterium Corynebacterium diphtheriae. […] The pathogenesis of diphtheria is based upon two primary determinants: 1. the ability of a given strain of C diphtheriae to colonize in the nasopharyngeal cavity and/or on the skin 2. its ability to produce diphtheria toxin. […] The structural gene for diphtheria toxin, tox, is carried by a family of closely related corynebacteriophages. […] Diphtheria toxin is extraordinarily potent: as little as 100 to 150 ng/kg of body weight is lethal. […] Intoxication of a single eukaryotic cell by diphtheria toxin can lead to complete irreversible inhibition of protein synthesis (by binding to elongation factor 2, EF-2).

• #11 Corynebacterium Diphtheriae – Medical Microbiology – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK7971/

  The structural gene for diphtheria toxin, tox, is carried by a family of closely related corynebacteriophages of which the -phage is the most extensively studied. The regulation of diphtheria tox expression is mediated by an iron-activated repressor, DtxR, which is encoded on the C diphtheriae genome. The expression of tox depends on the physiologic state of C diphtheriae. Under conditions in which iron becomes the growth-rate limiting substrate, iron dissociates from DtxR, the tox gene becomes derepressed, and diphtheria toxin is synthesized and secreted into the culture medium at maximal rates. […] Diphtheria toxin is extraordinarily potent; in sensitive species (e.g., humans, monkeys, rabbits, guinea pigs) as little as 100 to 150 ng/kg of body weight is lethal. Diphtheria toxin is composed of a single polypeptide chain of 535 amino acids. Biochemical genetic and X-ray crystallographic analysis show that the toxin is composed of three structural/functional domains: an N-terminal ADP-ribosyltransferase (catalytic domain); (2) a region which facilitates the delivery of the catalytic domain across the cell membrane (transmembrane domain); and (3) the eukaryotic cell receptor binding domain. Following mild digestion with trypsin and reduction under denaturing conditions, diphtheria toxin may be specifically cleaved in its protease-sensitive loop into two polypeptide fragments (A and B). Fragment A is the N-terminal 21 kDa component of the toxin and contains the catalytic center for the ADP-ribosylation of elongation factor 2 (EF-2) according to the following reaction:

• #12 June 2018 | Case of the Month Answer for Residency Program | UC Davis Department of Pathology

  https://health.ucdavis.edu/pathology/education/residency_program/caseofthemonth/201806/final.html

  The classical diphtheria infection results from inoculation of a host via sneezing or coughing of an infected third party. […] In addition to pseudomembranes, diphtheria is best known for neuropathies (including cranial nerve and oropharyngeal paralysis) and diffuse myocardiopathies (either present in 20-70% of patients). […] Produced in vivo by the bacteria, the toxin is a 58 kDa polypeptide composed of two fragments: Fragment A and Fragment B. […] Fragment B encodes the receptor and translocation binding domains, and has a role in allowing passage of diphtheria toxin into host cells. […] Fragment A, the biologically active portion, acts as a catalyst, transferring adenosine diphosphate ribose from NAD to Elongation Factor 2 (EF-2), thereby inactivating EF-2 and shutting down cellular protein synthesis.

• #13 Corynebacterium Diphtheriae – Medical Microbiology – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK7971/

  The structural gene for diphtheria toxin, tox, is carried by a family of closely related corynebacteriophages of which the -phage is the most extensively studied. The regulation of diphtheria tox expression is mediated by an iron-activated repressor, DtxR, which is encoded on the C diphtheriae genome. The expression of tox depends on the physiologic state of C diphtheriae. Under conditions in which iron becomes the growth-rate limiting substrate, iron dissociates from DtxR, the tox gene becomes derepressed, and diphtheria toxin is synthesized and secreted into the culture medium at maximal rates. […] Diphtheria toxin is extraordinarily potent; in sensitive species (e.g., humans, monkeys, rabbits, guinea pigs) as little as 100 to 150 ng/kg of body weight is lethal. Diphtheria toxin is composed of a single polypeptide chain of 535 amino acids. Biochemical genetic and X-ray crystallographic analysis show that the toxin is composed of three structural/functional domains: an N-terminal ADP-ribosyltransferase (catalytic domain); (2) a region which facilitates the delivery of the catalytic domain across the cell membrane (transmembrane domain); and (3) the eukaryotic cell receptor binding domain. Following mild digestion with trypsin and reduction under denaturing conditions, diphtheria toxin may be specifically cleaved in its protease-sensitive loop into two polypeptide fragments (A and B). Fragment A is the N-terminal 21 kDa component of the toxin and contains the catalytic center for the ADP-ribosylation of elongation factor 2 (EF-2) according to the following reaction:

• #14 Corynebacterium Diphtheriae – Medical Microbiology – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK7971/

  The structural gene for diphtheria toxin, tox, is carried by a family of closely related corynebacteriophages of which the -phage is the most extensively studied. The regulation of diphtheria tox expression is mediated by an iron-activated repressor, DtxR, which is encoded on the C diphtheriae genome. The expression of tox depends on the physiologic state of C diphtheriae. Under conditions in which iron becomes the growth-rate limiting substrate, iron dissociates from DtxR, the tox gene becomes derepressed, and diphtheria toxin is synthesized and secreted into the culture medium at maximal rates. […] Diphtheria toxin is extraordinarily potent; in sensitive species (e.g., humans, monkeys, rabbits, guinea pigs) as little as 100 to 150 ng/kg of body weight is lethal. Diphtheria toxin is composed of a single polypeptide chain of 535 amino acids. Biochemical genetic and X-ray crystallographic analysis show that the toxin is composed of three structural/functional domains: an N-terminal ADP-ribosyltransferase (catalytic domain); (2) a region which facilitates the delivery of the catalytic domain across the cell membrane (transmembrane domain); and (3) the eukaryotic cell receptor binding domain. Following mild digestion with trypsin and reduction under denaturing conditions, diphtheria toxin may be specifically cleaved in its protease-sensitive loop into two polypeptide fragments (A and B). Fragment A is the N-terminal 21 kDa component of the toxin and contains the catalytic center for the ADP-ribosylation of elongation factor 2 (EF-2) according to the following reaction:

• #15 June 2018 | Case of the Month Answer for Residency Program | UC Davis Department of Pathology

  https://health.ucdavis.edu/pathology/education/residency_program/caseofthemonth/201806/final.html

  The classical diphtheria infection results from inoculation of a host via sneezing or coughing of an infected third party. […] In addition to pseudomembranes, diphtheria is best known for neuropathies (including cranial nerve and oropharyngeal paralysis) and diffuse myocardiopathies (either present in 20-70% of patients). […] Produced in vivo by the bacteria, the toxin is a 58 kDa polypeptide composed of two fragments: Fragment A and Fragment B. […] Fragment B encodes the receptor and translocation binding domains, and has a role in allowing passage of diphtheria toxin into host cells. […] Fragment A, the biologically active portion, acts as a catalyst, transferring adenosine diphosphate ribose from NAD to Elongation Factor 2 (EF-2), thereby inactivating EF-2 and shutting down cellular protein synthesis.

• #16 Corynebacterium Diphtheriae – Medical Microbiology – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK7971/

  The intoxication of a single eukaryotic cell by diphtheria toxin involves at least four distinct steps: (1) the binding of the toxin to its cell surface receptor; (2) clustering of charged receptors into coated pits and internalization of the toxin by receptor-mediated endocytosis; following acidification of the endocytic vesicle by a membrane-associated, ATP-driven proton pump, (3) the insertion of the transmembrane domain into the membrane and the facilitated delivery of the catalytic domain to the cytosol, and (4) the ADP-ribosylation of EF-2, which results in the irreversible inhibition of protein synthesis. It has been shown that a single molecule of the catalytic domain delivered to the cytosol is sufficient to be lethal for the cell.

• #17 Mechanism of Diphtheria Toxin Catalytic Domain Delivery to the Eukaryotic Cell Cytosol and the Cellular Factors that Directly Participate in the Process

  https://www.mdpi.com/2072-6651/3/3/294

  The intoxication of sensitive eukaryotic cells by diphtheria toxin follows an ordered series of events. […] As the clathrin triskelon is replaced with a new set of protein components, including Arf-1 and COPI complex, the activity of the vacuolar (v)ATPase lowers the luminal pH of the EEVs. It is widely known that the acidification of the vesicle lumen triggers the dynamic unfolding of the transmembrane domain (T) which allows its insertion into the endosomal vesicle membrane forming a pore. […] While debate continues over the precise mechanism and requirements for this translocation event, it is widely accepted that the formation of this cation selective membrane pore is a critical step, without which translocation of the C-domain cannot occur. […] We have hypothesized that the C-domain of diphtheria toxin is threaded through the pore by a process which is facilitated by a Cytosolic Translocation Factor (CTF) complex.

• #18 Diphtheria – Wikipedia

  https://en.wikipedia.org/wiki/Diphtheria

  Diphtheria toxin (DT) is produced only by C. diphtheriae infected with a certain type of bacteriophage. Toxinogenicity is determined by phage conversion (also called lysogenic conversion); i.e., the ability of the bacterium to make DT changes as a consequence of infection by a particular phage. DT is encoded by the tox gene. Strains of corynephage are either tox+ (e.g., corynephage ) or tox (e.g., corynephage ). The tox gene becomes integrated into the bacterial genome. […] The diphtheria toxin precursor is a protein of molecular weight 60 kDa. Certain proteases, such as trypsin, selectively cleave DT to generate two peptide chains, amino-terminal fragment A (DT-A) and carboxyl-terminal fragment B (DT-B), which are held together by a disulfide bond. DT-B is a recognition subunit that gains entry of DT into the host cell by binding to the EGF-like domain of heparin-binding EGF-like growth factor on the cell surface. This signals the cell to internalize the toxin within an endosome via receptor-mediated endocytosis. Inside the endosome, DT is split by a trypsin-like protease into DT-A and DT-B. The acidity of the endosome causes DT-B to create pores in the endosome membrane, thereby catalyzing the release of DT-A into the cytoplasm.

• #19 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Diphtheria-Mechanism.aspx

  The symptoms of diphtheria are caused by a toxin that is released by the bacteria that cause the condition. […] The bacteria produce a toxin that kills cells in the throat. These cells then join to form the greywhite membrane that is typically seen in cases of diphtheria. The toxin can also spread via the bloodstream and cause damage to the nervous system and heart. […] Not all diphtheria bacteria produce the diphtheria toxin. Only those that are infected with a bacteriophage can produce the toxin. The bacteriophage transfers the genetic material that codes for the toxin into the bacterial DNA. […] The diphtheria toxin is a single polypeptide made up of fragment A and fragment B which are connected by a disulfide bond. Fragment B binds to the EGF-like domain of the heparin-binding EGF-like growth factor (HB-EGF) present on the surface of cells. This causes the cell to engulf the toxin inside an endosome, where it is divided into its two fragments. […] The acidic environment of the endosome triggers fragment B to make holes in the membrane of the endosome. This allows fragment A to be released, which moves into the cells cytoplasm where it prevents the formation of new proteins by interrupting an essential step in protein synthesis.

• #20 Corynebacterium diphtheriae | Mechanisms of Pathogenicity

  https://mechpath.com/2021/11/18/corynebacterium-diphtheriae/

  C. diphtheriae attaches to the cells and kills them by releasing its toxin, the Diphtheria Toxin (DT). […] Through this mechanism, C. diphtheriae damages the skin and the lining of the upper respiratory tract and throat. […] The most important virulence factor for C. diphtheriae is the DT. C. diphtheriae will secrete DT once it attaches to the cells lining the throat, the upper respiratory tract, or the skin. […] The binding of DT via the B subunit to the receptor causes the cell to take in the DT-receptor complex. This process is called endocytosis. […] By modifying this component, DT will make the host cell unable to make proteins needed for its survival. As a result, the DT affected cell will die, providing resources for the growth of C. diphtheriae.

• #21 Mechanism of Diphtheria Toxin Catalytic Domain Delivery to the Eukaryotic Cell Cytosol and the Cellular Factors that Directly Participate in the Process

  https://www.mdpi.com/2072-6651/3/3/294

  The intoxication of sensitive eukaryotic cells by diphtheria toxin follows an ordered series of events. […] As the clathrin triskelon is replaced with a new set of protein components, including Arf-1 and COPI complex, the activity of the vacuolar (v)ATPase lowers the luminal pH of the EEVs. It is widely known that the acidification of the vesicle lumen triggers the dynamic unfolding of the transmembrane domain (T) which allows its insertion into the endosomal vesicle membrane forming a pore. […] While debate continues over the precise mechanism and requirements for this translocation event, it is widely accepted that the formation of this cation selective membrane pore is a critical step, without which translocation of the C-domain cannot occur. […] We have hypothesized that the C-domain of diphtheria toxin is threaded through the pore by a process which is facilitated by a Cytosolic Translocation Factor (CTF) complex.

• #22 Azthena logo with the word Azthena

  https://www.news-medical.net/health/Diphtheria-Mechanism.aspx

  The symptoms of diphtheria are caused by a toxin that is released by the bacteria that cause the condition. […] The bacteria produce a toxin that kills cells in the throat. These cells then join to form the greywhite membrane that is typically seen in cases of diphtheria. The toxin can also spread via the bloodstream and cause damage to the nervous system and heart. […] Not all diphtheria bacteria produce the diphtheria toxin. Only those that are infected with a bacteriophage can produce the toxin. The bacteriophage transfers the genetic material that codes for the toxin into the bacterial DNA. […] The diphtheria toxin is a single polypeptide made up of fragment A and fragment B which are connected by a disulfide bond. Fragment B binds to the EGF-like domain of the heparin-binding EGF-like growth factor (HB-EGF) present on the surface of cells. This causes the cell to engulf the toxin inside an endosome, where it is divided into its two fragments. […] The acidic environment of the endosome triggers fragment B to make holes in the membrane of the endosome. This allows fragment A to be released, which moves into the cells cytoplasm where it prevents the formation of new proteins by interrupting an essential step in protein synthesis.

• #23 Corynebacterium Diphtheriae – Medical Microbiology – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK7971/

  The intoxication of a single eukaryotic cell by diphtheria toxin involves at least four distinct steps: (1) the binding of the toxin to its cell surface receptor; (2) clustering of charged receptors into coated pits and internalization of the toxin by receptor-mediated endocytosis; following acidification of the endocytic vesicle by a membrane-associated, ATP-driven proton pump, (3) the insertion of the transmembrane domain into the membrane and the facilitated delivery of the catalytic domain to the cytosol, and (4) the ADP-ribosylation of EF-2, which results in the irreversible inhibition of protein synthesis. It has been shown that a single molecule of the catalytic domain delivered to the cytosol is sufficient to be lethal for the cell.

• #24 Corynebacterium diphtheriae: Pathogenesis, Lab Diagnosis

  https://microbeonline.com/corynebacterium-diphtheriae-properties-pathogenesis-diagnosis/

  Corynebacterium diphtheriae is not an invasive organism. The pathogenesis of diphtheria is based on its potent exotoxin carried by lysogenized strains of C. diphtheriae. […] Like other exotoxins (botulinum, tetanus, cholera toxin), diphtheria toxin also has A and B subunits. The A or active subunit possesses the toxic activity, and the B or binding subunit is responsible for binding the exotoxin to specific receptors. […] The toxin binds to the cell surface via its binding subunit (B), and the active subunit (A) enters the cell. The active subunit is an enzyme that catalyzes the addition of ADP-ribose (ADP-R) to elongation factor-2 (EF-2). This inactivates EF-2, and protein synthesis is inhibited, leading to the death of host cells.

• #25 Diphtheria – Wikipedia

  https://en.wikipedia.org/wiki/Diphtheria

  Fragment A inhibits the synthesis of new proteins in the affected cell by catalyzing ADP-ribosylation of elongation factor EF-2a protein that is essential to the translation step of protein synthesis. This ADP-ribosylation involves the transfer of an ADP-ribose from NAD+ to a diphthamide (a modified histidine) residue within the EF-2 protein. Since EF-2 is needed for the moving of tRNA from the A-site to the P-site of the ribosome during protein translation, ADP-ribosylation of EF-2 prevents protein synthesis. […] ADP-ribosylation of EF-2 is reversed by giving high doses of nicotinamide (a form of vitamin B3), since this is one of the reaction’s end products, and high amounts drive the reaction in the opposite direction.

• #26 Diphtheria – Wikipedia

  https://en.wikipedia.org/wiki/Diphtheria

  Fragment A inhibits the synthesis of new proteins in the affected cell by catalyzing ADP-ribosylation of elongation factor EF-2a protein that is essential to the translation step of protein synthesis. This ADP-ribosylation involves the transfer of an ADP-ribose from NAD+ to a diphthamide (a modified histidine) residue within the EF-2 protein. Since EF-2 is needed for the moving of tRNA from the A-site to the P-site of the ribosome during protein translation, ADP-ribosylation of EF-2 prevents protein synthesis. […] ADP-ribosylation of EF-2 is reversed by giving high doses of nicotinamide (a form of vitamin B3), since this is one of the reaction’s end products, and high amounts drive the reaction in the opposite direction.

• #27 Corynebacterium Diphtheriae – Medical Microbiology – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK7971/

  The intoxication of a single eukaryotic cell by diphtheria toxin involves at least four distinct steps: (1) the binding of the toxin to its cell surface receptor; (2) clustering of charged receptors into coated pits and internalization of the toxin by receptor-mediated endocytosis; following acidification of the endocytic vesicle by a membrane-associated, ATP-driven proton pump, (3) the insertion of the transmembrane domain into the membrane and the facilitated delivery of the catalytic domain to the cytosol, and (4) the ADP-ribosylation of EF-2, which results in the irreversible inhibition of protein synthesis. It has been shown that a single molecule of the catalytic domain delivered to the cytosol is sufficient to be lethal for the cell.

• #28 Corynebacterium diphtheriae (Klebs-Löffler bacillus)- An Overview

  https://microbenotes.com/corynebacterium-diphtheriae/

  Toxin Fragment A inactivates EF-2 by catalyzing a reaction that yields free nicotinamide plus an inactive adenosine diphosphate-ribose-EF-2 complex (ADP-ribosylation). […] Because the turnover of EF-2 is very slow and approximately only one molecule per ribosome is present in a cell, it has been estimated that one exotoxin molecule can inactivate the entire EF-2 content in a cell, completely terminating host cell protein synthesis. […] It is assumed that the abrupt arrest of protein synthesis is responsible for the necrotizing and neurotoxic effects of diphtheria toxin. […] Toxin synthesis by lysogenized C diptheriae is regulated by a chromosomally encoded element, diphtheria toxin repressor (DTxR) which is activated in the presence of high iron concentrations, and can bind to the toxin gene operator and prevent toxin production. […] Low iron concentration and other factors such as osmolarity, amino acid concentrations and pH, however enhance the production of toxin.

• #29 Chapter 7: Diphtheria | Pink Book | CDC

  https://www.cdc.gov/pinkbook/hcp/table-of-contents/chapter-7-diphtheria.html

  Diphtheria is an acute, bacterial disease caused by toxin-producing strains of Corynebacterium diphtheriae. […] The organism produces a toxin that inhibits cellular protein synthesis and is responsible for local tissue destruction and formation of the pseudomembrane that is characteristic of this disease. […] The toxin is responsible for major complications such as myocarditis, polyneuropathies, and nephritis, and can also cause thrombocytopenia. […] The toxin produced at the site of the membrane is absorbed into the bloodstream and then distributed to the tissues of the body. […] Toxigenic diphtheria bacilli acquired in the nasopharynx produces a toxin that inhibits cellular protein synthesis, destroys local tissue, and forms a pseudomembrane. […] Non-toxin-producing C. diphtheriae strains cause mild to severe exudative pharyngitis and sometimes lesions, endocarditis, bacteremia, and septic arthritis.

• #30 Chapter 7: Diphtheria | Pink Book | CDC

  https://www.cdc.gov/pinkbook/hcp/table-of-contents/chapter-7-diphtheria.html

  Diphtheria is an acute, bacterial disease caused by toxin-producing strains of Corynebacterium diphtheriae. […] The organism produces a toxin that inhibits cellular protein synthesis and is responsible for local tissue destruction and formation of the pseudomembrane that is characteristic of this disease. […] The toxin is responsible for major complications such as myocarditis, polyneuropathies, and nephritis, and can also cause thrombocytopenia. […] The toxin produced at the site of the membrane is absorbed into the bloodstream and then distributed to the tissues of the body. […] Toxigenic diphtheria bacilli acquired in the nasopharynx produces a toxin that inhibits cellular protein synthesis, destroys local tissue, and forms a pseudomembrane. […] Non-toxin-producing C. diphtheriae strains cause mild to severe exudative pharyngitis and sometimes lesions, endocarditis, bacteremia, and septic arthritis.

• #31 Diptheria | PPT

  https://www.slideshare.net/slideshow/diptheria/45856276

  Diphtheria is a acute bacterial infection caused by Corynebacterium diphtheriae A gram positive bacillus It secretes a potent exotoxin major determinant of the pathogenicity Diphtheria is endemic in India Common below 15 years Mostly in winter and autumn seasons Both sexes are equally affected […] Pathogenesis Spreads through droplet infection during coughing, sneezing , talking Once infected remains infected till virulent bacilli are present in lesions, usually 2-4 weeks Diphtheria is a rapidly developing acute febrile illness with both local and systemic pathology […] Primary lesion in upper respiratory tract necrosis of epithelium injury leads to plasma leak, fibrin network formation with bacteria pseudo- membrane formation adherent to underlying tissue (nose, pharynx, larynx, tonsils) scraping leads to bleeding At this site they produce toxins that is absorbed and disseminate to whole body Exotoxin affects the heart, kidney, liver, spleen, muscle, peripheral nerves, adrenals

• #32 Diptheria | PPT

  https://www.slideshare.net/slideshow/diptheria/45856276

  Diphtheria is an acute toxin-mediated disease caused by Corynebacterium diphtheriae, which are gram-positive, catalase-positive rods. It is characterized by sore throat and an adherent membrane on the tonsils, pharynx, and/or nasal cavity. The membrane firmly adheres to the mucosa and can spread down the bronchial tree, causing respiratory obstruction. Humans are the only reservoir, and it is transmitted through respiratory droplets or direct contact. Treatment involves diphtheria antitoxin and antibiotics such as erythromycin. Childhood immunization is the main preventive measure. […] Corynebacterium diphtheriae produces an exotoxin that inhibits protein synthesis and causes pseudomembrane formation in the throat and other areas. Laboratory diagnosis involves microscopy, culture and toxin production testing. Immunization with diphtheria, tetanus and pertussis vaccine (DTP) provides active immunity against the disease.

• #33 Diptheria | PPT

  https://www.slideshare.net/slideshow/diptheria/45856276

  Diphtheria is a acute bacterial infection caused by Corynebacterium diphtheriae A gram positive bacillus It secretes a potent exotoxin major determinant of the pathogenicity Diphtheria is endemic in India Common below 15 years Mostly in winter and autumn seasons Both sexes are equally affected […] Pathogenesis Spreads through droplet infection during coughing, sneezing , talking Once infected remains infected till virulent bacilli are present in lesions, usually 2-4 weeks Diphtheria is a rapidly developing acute febrile illness with both local and systemic pathology […] Primary lesion in upper respiratory tract necrosis of epithelium injury leads to plasma leak, fibrin network formation with bacteria pseudo- membrane formation adherent to underlying tissue (nose, pharynx, larynx, tonsils) scraping leads to bleeding At this site they produce toxins that is absorbed and disseminate to whole body Exotoxin affects the heart, kidney, liver, spleen, muscle, peripheral nerves, adrenals

• #34 Chapter 7: Diphtheria | Pink Book | CDC

  https://www.cdc.gov/pinkbook/hcp/table-of-contents/chapter-7-diphtheria.html

  Diphtheria is an acute, bacterial disease caused by toxin-producing strains of Corynebacterium diphtheriae. […] The organism produces a toxin that inhibits cellular protein synthesis and is responsible for local tissue destruction and formation of the pseudomembrane that is characteristic of this disease. […] The toxin is responsible for major complications such as myocarditis, polyneuropathies, and nephritis, and can also cause thrombocytopenia. […] The toxin produced at the site of the membrane is absorbed into the bloodstream and then distributed to the tissues of the body. […] Toxigenic diphtheria bacilli acquired in the nasopharynx produces a toxin that inhibits cellular protein synthesis, destroys local tissue, and forms a pseudomembrane. […] Non-toxin-producing C. diphtheriae strains cause mild to severe exudative pharyngitis and sometimes lesions, endocarditis, bacteremia, and septic arthritis.

• #35 Diphtheria: Background, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/782051-overview

  Fragment A inhibits an amino acid transfer from RNA translocase to the ribosomal amino acid chain, thus inhibiting protein synthesis required for normal host cell functioning. […] DT causes a catalytic transfer of NAD to diphthamide, which inactivates the elongation factor, resulting in the inactivation eEF2, which results in protein synthesis blockage and subsequent cell death. […] Local tissue destruction enables the toxin to be carried lymphatically and hematologically to other parts of the body. Elaboration of the diphtheria toxin may affect distant organs such as the myocardium, kidneys, and nervous system.

• #36 Diphtheria – Symptoms & causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/diphtheria/symptoms-causes/syc-20351897

  Diphtheria is caused by the bacterium Corynebacterium diphtheriae. The bacterium usually multiplies on or near the surface of the throat or skin. C. diphtheriae spreads through: […] Diphtheria-causing bacteria may produce a toxin. This toxin damages tissue in the immediate area of infection usually, the nose and throat. At that site, the infection produces a tough, gray membrane made up of dead cells, bacteria and other substances. This membrane can obstruct breathing. […] The diphtheria toxin may spread through the bloodstream and damage other tissues in the body. For example, it can damage the heart muscle, causing such complications as inflammation of the heart muscle (myocarditis). Heart damage from myocarditis may be slight or severe. At its worst, myocarditis can lead to heart failure and sudden death.

• #37 Diphtheria – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK560911/

  The pathogenic impact of exotoxins extends to both localized and systemic manifestations of the disease. Viral bacteriophages carry the genetic code for exotoxins, facilitating their transmission among bacteria. […] The pathogenesis of diphtheria involves various etiological factors, including incomplete or absent immunization, waning immunity over time, low herd immunity, travel to endemic areas, travel to regions experiencing current epidemics, immunocompromised states, low socioeconomic status, large-scale population movements, overcrowded conditions, and domestic animals. […] Exotoxin production is the primary mechanism through which the organism manifests its distinctive clinical features. The exotoxin is a singular polypeptide composed of 2 subunits, A and B. The B subunit facilitates the toxin binding to the receptor on the cell membrane, while the A subunit possesses enzymatic properties, cleaving nicotinamide from nicotinamide adenine dinucleotide (NAD). This cleavage inhibits protein synthesis through adenosine diphosphate (ADP)-ribosylation of elongation factor 2 (EF-2). The host’s response to the bacteria induces local inflammation in the throat and pharynx, giving rise to a resilient, gray pseudomembranean identifiable hallmark of the disease. […] Local tissue destruction facilitates the lymphatic and hematologic spread of the toxin to various body systems. This diphtheria toxin may damage distant organs, including the kidneys, myocardium, and the nervous system.

• #38 Diphtheria | Queensland Health

  https://www.health.qld.gov.au/cdcg/index/diphtheria

  Diphtheria is a disease caused primarily by toxigenic Corynebacterium diphtheriae bacteria, a gram-positive bacillus. Toxigenicity occurs when the bacillus becomes infected with a specific virus (corynebacteriophage) which carries the gene for the toxin (tox gene). The potent exotoxin is the major virulence mechanism leading to human disease. […] The toxin causes local tissue necrosis and is associated with the development of a pseudomembrane at the back of the throat in respiratory disease and may cause severe systemic manifestations. […] Systemic manifestations are due primarily to toxic effects of diphtheria toxin. Cardiac effects, such as dysrhythmias, conduction disturbances and dilated cardiomyopathy, usually present 7-14 days after the onset of respiratory symptoms in 10-25% of cases.

• #39 Diphtheria – Infectious Disease Advisor

  https://www.infectiousdiseaseadvisor.com/ddi/diphtheria/

  Diphtheria is a potentially fatal disease caused by infection with toxin-producing strains of Corynebacterium diphtheriae, a Gram-positive bacillus. […] The most serious, potentially life-threatening complications of diphtheria, which include myocarditis, are caused by diphtheria toxin, an exotoxin that inhibits protein synthesis and causes cell death. […] Diphtheria toxin causes the manifestations of diphtheria. Specifically, this toxin block protein synthesis, cause local tissue destruction, and drives the formation of the hallmark pseudomembrane. […] Most complications from diphtheria infection are caused by the diphtheria toxin. As the bacteria produce the toxin in the upper respiratory tract, it is absorbed into the bloodstream and then distributed to the body tissues. […] Approximately 10% to 25% of patients with diphtheria develop cardiac complications frequently myocarditis during the acute phase or within the weeks following infection.

• #40 Diphtheria – Respirology – Diseases – McMaster Textbook of Internal Medicine

  https://empendium.com/mcmtextbook/chapter/B31.II.3.67.

  Diphtheria is a rare (5 cases per year in Canada) acute bacterial infection caused by Corynebacterium diphtheriae that usually affects the upper respiratory tract or skin. In some cases it may lead to cardiac, central nervous system (CNS), or renal complications. […] The bacteria multiply at the port of entry and produce an exotoxin, which causes localized lesions in the respiratory epithelium, leading to the development of pseudomembranes, and spreads to organs distant from the site of infection via blood and the lymphatic system. The toxin inhibits protein synthesis, resulting in cell death. Nontoxigenic C diphtheriae strains cause invasive disease. […] Neurologic toxicity can occur in 5% of patients with mild disease and in 75% of patients with severe disease. Paralysis of the soft palate and posterior pharyngeal wall is followed by cranial neuropathies. Peripheral neuropathies can occur weeks to months later and can include paralysis of respiratory muscles, sensory neuropathy, and the stock-and-glove pattern. […] The severity of membrane formation correlates with the onset of symptoms and delay in administration of antitoxin.

• #41 Diphtheria – Symptoms & causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/diphtheria/symptoms-causes/syc-20351897

  The toxin can also cause nerve damage. Typical targets are nerves to the throat, where poor nerve conduction may cause difficulty swallowing. Nerves to the arms and legs also may become inflamed, causing muscle weakness. […] If the diphtheria toxin damages the nerves that help control muscles used in breathing, these muscles may become paralyzed. At that point, you might need mechanical assistance to breathe.

• #42 Diphtheria – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK560911/

  The pathogenic impact of exotoxins extends to both localized and systemic manifestations of the disease. Viral bacteriophages carry the genetic code for exotoxins, facilitating their transmission among bacteria. […] The pathogenesis of diphtheria involves various etiological factors, including incomplete or absent immunization, waning immunity over time, low herd immunity, travel to endemic areas, travel to regions experiencing current epidemics, immunocompromised states, low socioeconomic status, large-scale population movements, overcrowded conditions, and domestic animals. […] Exotoxin production is the primary mechanism through which the organism manifests its distinctive clinical features. The exotoxin is a singular polypeptide composed of 2 subunits, A and B. The B subunit facilitates the toxin binding to the receptor on the cell membrane, while the A subunit possesses enzymatic properties, cleaving nicotinamide from nicotinamide adenine dinucleotide (NAD). This cleavage inhibits protein synthesis through adenosine diphosphate (ADP)-ribosylation of elongation factor 2 (EF-2). The host’s response to the bacteria induces local inflammation in the throat and pharynx, giving rise to a resilient, gray pseudomembranean identifiable hallmark of the disease. […] Local tissue destruction facilitates the lymphatic and hematologic spread of the toxin to various body systems. This diphtheria toxin may damage distant organs, including the kidneys, myocardium, and the nervous system.

• #43 Chapter 7: Diphtheria | Pink Book | CDC

  https://www.cdc.gov/pinkbook/hcp/table-of-contents/chapter-7-diphtheria.html

  Diphtheria is an acute, bacterial disease caused by toxin-producing strains of Corynebacterium diphtheriae. […] The organism produces a toxin that inhibits cellular protein synthesis and is responsible for local tissue destruction and formation of the pseudomembrane that is characteristic of this disease. […] The toxin is responsible for major complications such as myocarditis, polyneuropathies, and nephritis, and can also cause thrombocytopenia. […] The toxin produced at the site of the membrane is absorbed into the bloodstream and then distributed to the tissues of the body. […] Toxigenic diphtheria bacilli acquired in the nasopharynx produces a toxin that inhibits cellular protein synthesis, destroys local tissue, and forms a pseudomembrane. […] Non-toxin-producing C. diphtheriae strains cause mild to severe exudative pharyngitis and sometimes lesions, endocarditis, bacteremia, and septic arthritis.

• #44 Diphtheria – Symptoms & causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/diphtheria/symptoms-causes/syc-20351897

  The toxin can also cause nerve damage. Typical targets are nerves to the throat, where poor nerve conduction may cause difficulty swallowing. Nerves to the arms and legs also may become inflamed, causing muscle weakness. […] If the diphtheria toxin damages the nerves that help control muscles used in breathing, these muscles may become paralyzed. At that point, you might need mechanical assistance to breathe.

• #45 Corynebacterium diphtheriae (Klebs-Löffler bacillus)- An Overview

  https://microbenotes.com/corynebacterium-diphtheriae/

  Toxin Fragment A inactivates EF-2 by catalyzing a reaction that yields free nicotinamide plus an inactive adenosine diphosphate-ribose-EF-2 complex (ADP-ribosylation). […] Because the turnover of EF-2 is very slow and approximately only one molecule per ribosome is present in a cell, it has been estimated that one exotoxin molecule can inactivate the entire EF-2 content in a cell, completely terminating host cell protein synthesis. […] It is assumed that the abrupt arrest of protein synthesis is responsible for the necrotizing and neurotoxic effects of diphtheria toxin. […] Toxin synthesis by lysogenized C diptheriae is regulated by a chromosomally encoded element, diphtheria toxin repressor (DTxR) which is activated in the presence of high iron concentrations, and can bind to the toxin gene operator and prevent toxin production. […] Low iron concentration and other factors such as osmolarity, amino acid concentrations and pH, however enhance the production of toxin.

• #46 Corynebacterium diphtheriae (Klebs-Löffler bacillus)- An Overview

  https://microbenotes.com/corynebacterium-diphtheriae/

  Toxin Fragment A inactivates EF-2 by catalyzing a reaction that yields free nicotinamide plus an inactive adenosine diphosphate-ribose-EF-2 complex (ADP-ribosylation). […] Because the turnover of EF-2 is very slow and approximately only one molecule per ribosome is present in a cell, it has been estimated that one exotoxin molecule can inactivate the entire EF-2 content in a cell, completely terminating host cell protein synthesis. […] It is assumed that the abrupt arrest of protein synthesis is responsible for the necrotizing and neurotoxic effects of diphtheria toxin. […] Toxin synthesis by lysogenized C diptheriae is regulated by a chromosomally encoded element, diphtheria toxin repressor (DTxR) which is activated in the presence of high iron concentrations, and can bind to the toxin gene operator and prevent toxin production. […] Low iron concentration and other factors such as osmolarity, amino acid concentrations and pH, however enhance the production of toxin.

• #47 Diphtheria toxin: The nuts and bolts – The Native Antigen Company

  https://thenativeantigencompany.com/diphtheria-toxin-the-nuts-and-bolts/

  Considering C. diphtheriae cells can produce 5,000 molecules of exotoxin/hour, it is no surprise that a sustained infection can cause widespread damage to organs and the nervous system. […] Over the past five decades, a lot of effort has been invested in studying DTs mechanism of action and the way it contributes to pathogenicity. […] One of DTs unique properties is its ability to transport proteins across mammalian cell membranes, which are otherwise impermeable to large molecules. […] By truncating and fusing DTs membrane translocation domain with other genes, it can therefore be used as a transporter of protein payloads. […] Combined with DTs ability to inactivate ribosomal machinery, this has led researchers to explore its potential in basic research and pharmaceutical applications.

• #48 Biomarkers of Vaccine Safety and Efficacy for Diphtheria Vaccines | FDA

  https://www.fda.gov/vaccines-blood-biologics/science-research-biologics/biomarkers-vaccine-safety-and-efficacy-diphtheria-vaccines

  Corynebacterium diphtheriae is a gram-positive bacterium and the cause of the severe respiratory disease diphtheria. Diphtheria toxin (DT), the primary virulence determinant for this pathogen, has been extensively investigated; however, factors involved in the colonization and survival of this organism on the mucosal surfaces of the human host have not been well characterized. […] A better understanding of the fundamental mechanisms of pathogenesis of C. diphtheriae will facilitate the development of future vaccines that are directed not only against the toxin, but also to other virulence determinants. […] C. diphtheriae uses host compounds such as heme and hemoglobin as essential iron sources, and it also requires metals such as zinc (Zn) and manganese (Mn) for survival in the human host.

• #49 Biomarkers of Vaccine Safety and Efficacy for Diphtheria Vaccines | FDA

  https://www.fda.gov/vaccines-blood-biologics/science-research-biologics/biomarkers-vaccine-safety-and-efficacy-diphtheria-vaccines

  Heme uptake in C. diphtheriae involves an ABC-type heme transporter as well as various surface-anchored proteins such as HtaA, ChtA and ChtC. […] Deletion analysis of htaA and the hmuTUV genes, which encode an ABC-type heme transporter, indicates that the products of these genes are involved in heme transport in C. diphtheriae, and further suggests that HtaA functions as a cell surface receptor for heme and heme-containing proteins in C. diphtheriae. […] Heme that has entered the cytosol of C. diphtheriae is proposed to be degraded by the heme oxygenase enzyme, HmuO, which releases the heme-associated iron. […] The ChrSA and HrrSA two-component signal transduction systems in C. diphtheriae regulate expression of the hmuO gene by a heme-dependent manner; recent studies by our group have shown that these systems also controls the expression of additional operons in C. diphtheriae through a similar regulatory mechanism.

• #50 Biomarkers of Vaccine Safety and Efficacy for Diphtheria Vaccines | FDA

  https://www.fda.gov/vaccines-blood-biologics/science-research-biologics/biomarkers-vaccine-safety-and-efficacy-diphtheria-vaccines

  Heme uptake in C. diphtheriae involves an ABC-type heme transporter as well as various surface-anchored proteins such as HtaA, ChtA and ChtC. […] Deletion analysis of htaA and the hmuTUV genes, which encode an ABC-type heme transporter, indicates that the products of these genes are involved in heme transport in C. diphtheriae, and further suggests that HtaA functions as a cell surface receptor for heme and heme-containing proteins in C. diphtheriae. […] Heme that has entered the cytosol of C. diphtheriae is proposed to be degraded by the heme oxygenase enzyme, HmuO, which releases the heme-associated iron. […] The ChrSA and HrrSA two-component signal transduction systems in C. diphtheriae regulate expression of the hmuO gene by a heme-dependent manner; recent studies by our group have shown that these systems also controls the expression of additional operons in C. diphtheriae through a similar regulatory mechanism.

• #51 June 2018 | Case of the Month Answer for Residency Program | UC Davis Department of Pathology

  https://health.ucdavis.edu/pathology/education/residency_program/caseofthemonth/201806/final.html

  It is the activity of Fragment A that leads to host cell death. […] Generation of the toxin is not native to the Corynebacterium proteome (i.e. in their normal state, C. diphtheriae are negative for the diphtheria toxin gene). […] A bacteriophage (-corynephage) carries the tox gene, which can infect a C. diphtheriae cell and integrate its nucleic acids into the bacterial genome (a process called lysogeny). […] While the exact pathogenesis of non-toxigenic C. diphtheriae endocardial infections is not known, it is believed that variations in the adhesive pili on the bacterial surface play a role in enhancing the ability of the bacterium to penetrate the respiratory epithelial barrier and enter the bloodstream. […] The bacteria are either phagocytosed by epithelial cells (normally a non-phagocytic cell), or pass directly through the cytoplasm, later resulting in epithelial cell death.

• #52 Chapter 7: Diphtheria | Pink Book | CDC

  https://www.cdc.gov/pinkbook/hcp/table-of-contents/chapter-7-diphtheria.html

  Diphtheria is an acute, bacterial disease caused by toxin-producing strains of Corynebacterium diphtheriae. […] The organism produces a toxin that inhibits cellular protein synthesis and is responsible for local tissue destruction and formation of the pseudomembrane that is characteristic of this disease. […] The toxin is responsible for major complications such as myocarditis, polyneuropathies, and nephritis, and can also cause thrombocytopenia. […] The toxin produced at the site of the membrane is absorbed into the bloodstream and then distributed to the tissues of the body. […] Toxigenic diphtheria bacilli acquired in the nasopharynx produces a toxin that inhibits cellular protein synthesis, destroys local tissue, and forms a pseudomembrane. […] Non-toxin-producing C. diphtheriae strains cause mild to severe exudative pharyngitis and sometimes lesions, endocarditis, bacteremia, and septic arthritis.

• #53 June 2018 | Case of the Month Answer for Residency Program | UC Davis Department of Pathology

  https://health.ucdavis.edu/pathology/education/residency_program/caseofthemonth/201806/final.html

  It is the activity of Fragment A that leads to host cell death. […] Generation of the toxin is not native to the Corynebacterium proteome (i.e. in their normal state, C. diphtheriae are negative for the diphtheria toxin gene). […] A bacteriophage (-corynephage) carries the tox gene, which can infect a C. diphtheriae cell and integrate its nucleic acids into the bacterial genome (a process called lysogeny). […] While the exact pathogenesis of non-toxigenic C. diphtheriae endocardial infections is not known, it is believed that variations in the adhesive pili on the bacterial surface play a role in enhancing the ability of the bacterium to penetrate the respiratory epithelial barrier and enter the bloodstream. […] The bacteria are either phagocytosed by epithelial cells (normally a non-phagocytic cell), or pass directly through the cytoplasm, later resulting in epithelial cell death.

• #54 Diphtheria | Queensland Health

  https://www.health.qld.gov.au/cdcg/index/diphtheria

  While antibiotics are necessary, diphtheria antitoxin (DAT) is considered the mainstay of preventing toxin related complications of respiratory disease. […] DAT neutralises circulating toxin. DAT is considered the mainstay of treatment for respiratory diphtheria, while antibiotics are required to eradicate the organism, stop further toxin production, and help prevent transmission. Toxin already bound to tissue is unaffected, meaning DAT does not reverse symptoms caused by bound toxin. Rather, it limits disease progression making early administration critical, with the degree of protection being inversely proportional to delay in administration.

• #55 Diphtheria | Queensland Health

  https://www.health.qld.gov.au/cdcg/index/diphtheria

  While antibiotics are necessary, diphtheria antitoxin (DAT) is considered the mainstay of preventing toxin related complications of respiratory disease. […] DAT neutralises circulating toxin. DAT is considered the mainstay of treatment for respiratory diphtheria, while antibiotics are required to eradicate the organism, stop further toxin production, and help prevent transmission. Toxin already bound to tissue is unaffected, meaning DAT does not reverse symptoms caused by bound toxin. Rather, it limits disease progression making early administration critical, with the degree of protection being inversely proportional to delay in administration.

• #56 Diphtheria | Queensland Health

  https://www.health.qld.gov.au/cdcg/index/diphtheria

  While antibiotics are necessary, diphtheria antitoxin (DAT) is considered the mainstay of preventing toxin related complications of respiratory disease. […] DAT neutralises circulating toxin. DAT is considered the mainstay of treatment for respiratory diphtheria, while antibiotics are required to eradicate the organism, stop further toxin production, and help prevent transmission. Toxin already bound to tissue is unaffected, meaning DAT does not reverse symptoms caused by bound toxin. Rather, it limits disease progression making early administration critical, with the degree of protection being inversely proportional to delay in administration.

• #57 Diphtheria: Causes, Symptoms, Treatment & Prevention

  https://my.clevelandclinic.org/health/diseases/17870-diphtheria

  Diphtheria is a contagious infection caused by a bacterium called Corynebacterium diphtheriae. The bacterium releases a toxin that causes a buildup of grey tissue in your throat, leading to problems with swallowing and breathing. […] Diphtheria is caused by bacteria adhering to the lining of your respiratory system. These bacteria generate a toxin that damages your respiratory tissue cells. Within two or three days, the tissue left behind forms a bulky, grey coating. This coating has the potential to cover tissues in your voice box, throat, nose and tonsils. For the infected person, breathing and swallowing become hard to do. […] Diphtheria treatment begins immediately sometimes even before the lab test results are confirmed. Your healthcare provider will prescribe diphtheria antitoxin to stop damage to your organs. Theyll also prescribe antibiotics, typically penicillin or erythromycin, to fight infection.

• #58

  https://link.springer.com/article/10.1186/s12982-024-00352-1

  The extracellular protein of C. diphtheriae, known as diphtheria toxin, prevents the creation of new proteins and destroys vulnerable cells. […] Clinical manifestations can be local or systemic, with local signs including pseudomembrane production at the colonization site and sore throat. […] The overall case fatality ratio for diphtheria ranges from 5 to 10%, with neurological complications observed in approximately three-quarters of severe cases. […] Vaccination remains the most effective method of prevention, and strengthening routine immunization programs, especially in low- and middle-income countries (LMICs), is essential to achieving high coverage rates.

• #59 Diptheria | PPT

  https://www.slideshare.net/slideshow/diptheria/45856276

  Diphtheria is an acute toxin-mediated disease caused by Corynebacterium diphtheriae, which are gram-positive, catalase-positive rods. It is characterized by sore throat and an adherent membrane on the tonsils, pharynx, and/or nasal cavity. The membrane firmly adheres to the mucosa and can spread down the bronchial tree, causing respiratory obstruction. Humans are the only reservoir, and it is transmitted through respiratory droplets or direct contact. Treatment involves diphtheria antitoxin and antibiotics such as erythromycin. Childhood immunization is the main preventive measure. […] Corynebacterium diphtheriae produces an exotoxin that inhibits protein synthesis and causes pseudomembrane formation in the throat and other areas. Laboratory diagnosis involves microscopy, culture and toxin production testing. Immunization with diphtheria, tetanus and pertussis vaccine (DTP) provides active immunity against the disease.

• #60

  https://link.springer.com/article/10.1186/s12982-024-00352-1

  The extracellular protein of C. diphtheriae, known as diphtheria toxin, prevents the creation of new proteins and destroys vulnerable cells. […] Clinical manifestations can be local or systemic, with local signs including pseudomembrane production at the colonization site and sore throat. […] The overall case fatality ratio for diphtheria ranges from 5 to 10%, with neurological complications observed in approximately three-quarters of severe cases. […] Vaccination remains the most effective method of prevention, and strengthening routine immunization programs, especially in low- and middle-income countries (LMICs), is essential to achieving high coverage rates.

• #61 Challenges of Diphtheria Toxin Detection

  https://www.mdpi.com/2072-6651/16/6/245

  The immunodiffusion (or immunoprecipitation) assay commonly called Elek test was developed by Orjan Ouchterlony and Stephen D. Elek independently in 1948. […] The test is based on a precipitation phenomenon that occurs between the toxin and the antitoxin, creating visible precipitation lines on semi-solid media. […] The first modification of the Elek test was proposed by Feldman et al. […] The immunoblot detection can be characterised by a low percentage of false positive results for nonspecific binding. […] The limit of detection is 20.8 nM of the target (tox gene fragment) in 5 min or 0.5 nM in 30 min. […] The detection of the toxin is the most important test in the microbiological diagnosis of diphtheria. […] The challenges in the development of new test for DT detection include, among others, the following: (i) the test should be independent of the availability of diphtheria antitoxin; (ii) it should be easy-to-perform and the results should be easy-to-interpret so that local laboratories would be able to carry out the test even without any experience in diphtheria diagnostics; (iii) it should be rapid; (iv) it might be implemented as a point-of-care test, especially in cases when an outbreak is suspected; and (v) it should be easy to store and maintain activity for long time because diphtheria cases occur very rarely in some countries.

• #62 Challenges of Diphtheria Toxin Detection

  https://www.mdpi.com/2072-6651/16/6/245

  The immunodiffusion (or immunoprecipitation) assay commonly called Elek test was developed by Orjan Ouchterlony and Stephen D. Elek independently in 1948. […] The test is based on a precipitation phenomenon that occurs between the toxin and the antitoxin, creating visible precipitation lines on semi-solid media. […] The first modification of the Elek test was proposed by Feldman et al. […] The immunoblot detection can be characterised by a low percentage of false positive results for nonspecific binding. […] The limit of detection is 20.8 nM of the target (tox gene fragment) in 5 min or 0.5 nM in 30 min. […] The detection of the toxin is the most important test in the microbiological diagnosis of diphtheria. […] The challenges in the development of new test for DT detection include, among others, the following: (i) the test should be independent of the availability of diphtheria antitoxin; (ii) it should be easy-to-perform and the results should be easy-to-interpret so that local laboratories would be able to carry out the test even without any experience in diphtheria diagnostics; (iii) it should be rapid; (iv) it might be implemented as a point-of-care test, especially in cases when an outbreak is suspected; and (v) it should be easy to store and maintain activity for long time because diphtheria cases occur very rarely in some countries.

Zobacz więcej