Diphtheria
is an acute, toxin-mediated disease caused by the bacterium Corynebacterium
diphtheria, an aerobic gram-positive bacillus. The name of the disease is
derived from the Greek diphtheria, meaning leather hide. The disease was
described in the 5th century BCE by Hippocrates. The bacterium was first
observed in diphtheritic membranes by Klebs in 1883 and cultivated by Löffler
in 1884.1  

 

The micro-organism’s
pathogenic activity is mediated by the Diphtheria toxin (DT) – an extracellular
protein of Corynebacterium diphtheria that inhibits protein synthesis and kills
susceptible cells, including myocardial cells causing a myocarditis. The most
common presentation is an upper respiratory tract infection with marked
inflammation and formation of pseudo-membranes on the respiratorymucosal surfaces.
 The gene that encodes DT (tox) is
present in some corynephages, and DT is only produced by C. diphtheria isolates
that harbour tox+ phages. 2

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Antitoxin
produced in horses was invented in the late 19th century and neutralises
circulating unbound toxin after infection. In 1909, Theobald Smith proposed
that nontoxic mixtures of DT and diphtheria antitoxin at equivalence could be
used for active immunization of humans against diphtheria. A successful
large-scale trial of toxin-antitoxin vaccine was conducted in 1922 in New York
City by W. H. Park.2

 

Toxoid
was developed in the 1920s and is essentially formalin-treated
DT. Diphtheria toxoid is produced by growing toxigenic C. diphtheria in liquid
medium.
Filtrates
from cultures of C. diphtheria contain a potent heat-labile diphtheria toxin
(DT).2  In 1923, Ramon discovered that treatment with
formalin eliminated the toxicity of DT without destroying its immunogenicity.2 The filtrate is incubated with
formaldehyde to convert toxin to toxoid and is then adsorbed onto an aluminum
salt.1

 

 

In 1935,
Guthrie, M.B. described the production of Corynebacterium diphtheria vaccine
from clinical isolates of Corynebacterium obtained by culture in Loeffler’s
serum medium, as follows: After incubation at 37oC for twenty-four
hours films are prepared, stained, and examined for the presence of K.L.B. Pure
cultures are obtained if possible, but this is sometimes difficult if only a
few K.L.B. are present. A suspension of the culture is made in normal saline,
and heated to 550 to 600C. for thirty minutes. It is then
subcultured on the same type of medium, incubated for 48 hours at 370C,
and examined for sterility. When sterile the saline suspension is diluted with
0.5 per cent. Carbol saline to contain approximately 100 million organisms per
cubic centimetre. The method of standardizing is done by using Browin’s
standard opacity tubes, or Wright’s method. It is essential that the strictest
aseptic precautions be taken during the different stages and the final product
tested for sterility, whether in sealed ampoules or rubber-capped bottles. The
vaccine prepared by the above method must be used always in conjunction with suitable
doses of anti- toxin.3  

 

Identification
of the structural gene for diphtheria toxin and the immediately contiguous
upstream regulatory sequences was accomplished during the 1980s with cloning of
the gene encoding the DT receptor and identification of the gene product as the
heparin-binding epidermal growth factor precursor (HB-EGF precursor)2

 

Toxigenic
Corynebacterium diphtheria infected with phage virus can be engineered to
uptake these genes and re-infected into new cells (such as non-toxigenic
strains of Corynebacterium) where the genetic machinery and protein synthesis
has been overtaken by the virus. Toxin production (toxigenicity) occurs only
when the bacillus is itself infected (lysogenized) by a specific virus
(bacteriophage) carrying the genetic information for the toxin (tox gene). This
would allow for large scale toxin protein production.

 

Molecular
analysis of tox genes has revealed several tox alleles that encode identical DT
proteins. Therefore, isolates of C. diphtheria produce a single antigenic type
of DT, and diphtheria toxoid continues to be an effective vaccine for
immunization against diphtheria.2

 

 

 

 

 

 

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