''Corynebacterium diphtheriae'' is the
pathogenic bacterium
Pathogenic bacteria are bacteria that can cause disease. This article focuses on the bacteria that are pathogenic to humans. Most species of bacteria are harmless and are often beneficial but others can cause infectious diseases. The number of t ...
that causes
diphtheria
Diphtheria is an infection caused by the bacterium '' Corynebacterium diphtheriae''. Most infections are asymptomatic or have a mild clinical course, but in some outbreaks more than 10% of those diagnosed with the disease may die. Signs and s ...
.
It is also known as the Klebs–Löffler bacillus, because it was discovered in 1884 by German
bacteriologist
A bacteriologist is a microbiologist, or similarly trained professional, in bacteriology -- a subdivision of microbiology that studies bacteria, typically pathogenic ones. Bacteriologists are interested in studying and learning about bacteria, ...
s
Edwin Klebs
Theodor Albrecht Edwin Klebs (6 February 1834 – 23 October 1913) was a German-Swiss microbiologist. He is mainly known for his work on infectious diseases. His works paved the way for the beginning of modern bacteriology, and inspired Louis ...
(1834–1912) and
Friedrich Löffler (1852–1915).
The bacteria are usually harmless unless they are infected by a
bacteriophage
A bacteriophage (), also known informally as a ''phage'' (), is a duplodnaviria virus that infects and replicates within bacteria and archaea. The term was derived from "bacteria" and the Greek φαγεῖν ('), meaning "to devour". Bacteri ...
that carries a
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
that gives rise to a
toxin
A toxin is a naturally occurring organic poison produced by metabolic activities of living cells or organisms. Toxins occur especially as a protein or conjugated protein. The term toxin was first used by organic chemist Ludwig Brieger (1849– ...
.
This toxin causes the disease.
Diphtheria is caused by the adhesion and infiltration of the bacteria into the mucosal layers of the body, primarily affecting the respiratory tract and the subsequent release of an endotoxin.
The toxin has a localized effect on skin lesions, as well as a metastatic, proteolytic effects on other organ systems in severe infections.
Originally a major cause of childhood mortality, diphtheria has been almost entirely eradicated due to the vigorous administration of the diphtheria vaccination in the 1910s.
Diphtheria is no longer transmitted as frequently due to the development of the vaccine, DTaP. Although diphtheria outbreaks continue to occur, this often in developing countries where the majority of the population is not vaccinated.
Classification
Four subspecies are recognized: ''C. d. mitis'', ''C. d. intermedius'', ''C. d. gravis'', and ''C. d. belfanti''. The four subspecies differ slightly in their
colonial morphology
In microbiology, colonial morphology refers to the visual appearance of bacterial or fungal colonies on an agar plate. Examining colonial morphology is the first step in the identification of an unknown microbe. The systematic assessment of the c ...
and biochemical properties, such as the ability to metabolize certain nutrients. All may be toxigenic (and therefore cause diphtheria) or not toxigenic.
Strain subtyping involves comparing species of bacteria and categorizing them into subspecies. Strain subtyping also helps with identifying the origin of a certain bacteria’s outbreak. However, when it comes to the subtyping of ''C. diphtheriae'', there is not a lot of useful or accurate classification due to the lack of publicly available resources to identify strains and therefore finding the origin of outbreaks.
Toxin
''C. diphtheriae'' produces diphtheria toxin which alters protein function in the host by inactivating the
elongation factor
Elongation factors are a set of proteins that function at the ribosome, during protein synthesis, to facilitate translational elongation from the formation of the first to the last peptide bond of a growing polypeptide. Most common elongation f ...
EF-2. This causes pharyngitis and 'pseudomembrane' in the throat. The strains which are toxigenic are ones which have been infected with a
bacteriophage
A bacteriophage (), also known informally as a ''phage'' (), is a duplodnaviria virus that infects and replicates within bacteria and archaea. The term was derived from "bacteria" and the Greek φαγεῖν ('), meaning "to devour". Bacteri ...
.
The
diphtheria toxin
Diphtheria toxin is an exotoxin secreted by '' Corynebacterium diphtheriae'', the pathogenic bacterium that causes diphtheria. The toxin gene is encoded by a prophageA prophage is a virus that has inserted itself into the genome of the host ...
gene is encoded by the bacteriophage found in toxigenic strains, integrated into the bacterial chromosome.
The diphtheria toxin repressor is mainly controlled by iron. It serves as the essential cofactor for the activation of target DNA binding. A
low concentration of iron is required in the medium for toxin production. At high iron concentrations, iron molecules bind to an
aporepressor
In molecular genetics, a repressor is a DNA- or RNA-binding protein that inhibits the expression of one or more genes by binding to the operator or associated silencers. A DNA-binding repressor blocks the attachment of RNA polymerase to the ...
on the beta
bacteriophage
A bacteriophage (), also known informally as a ''phage'' (), is a duplodnaviria virus that infects and replicates within bacteria and archaea. The term was derived from "bacteria" and the Greek φαγεῖν ('), meaning "to devour". Bacteri ...
, which carries the ''Tox'' gene. When bound to iron, the aporepressor shuts down toxin production.
Elek's test for toxigenicity is used to determine whether the organism is able to produce the diphtheria toxin.
Identification
To identify ''C. diphtheriae'', a
Gram stain
In microbiology and bacteriology, Gram stain (Gram staining or Gram's method), is a method of staining used to classify bacterial species into two large groups: gram-positive bacteria and gram-negative bacteria. The name comes from the Danish b ...
is performed to show
Gram-positive
In bacteriology, gram-positive bacteria are bacteria that give a positive result in the Gram stain test, which is traditionally used to quickly classify bacteria into two broad categories according to their type of cell wall.
Gram-positive bact ...
, highly
pleomorphic organisms often looking like Chinese letters. Stains like
Albert's stain and
Ponder's stain are used to demonstrate the
metachromatic Metachromasia (var. metachromasy) is a characteristical change in the color of staining carried out in biological tissues, exhibited by certain dyes when they bind to particular substances present in these tissues, called chromotropes. For example ...
granules formed in the polar regions. The granules are called polar granules, Babes Ernst granules or
volutin granules Volutin granules are an intracytoplasmic storage form of complexed inorganic polyphosphate, the production of which is used as one of the identifying criteria when attempting to isolate ''Corynebacterium diphtheriae'' on Löffler's medium. Polypho ...
. An enrichment medium, such as
Löffler's medium Löffler's medium is a special substance used to grow diphtheria bacilli to confirm the diagnosis.
History
In 1887, Friedrich Loeffler devised a culture medium containing horse serum, meat infusion, and dextrose for use in the cultivation of co ...
, is used to preferentially grow ''C. diphtheriae''. After that, a differential plate known as
tellurite agar, allows all ''Corynebacteria'' (including ''C. diphtheriae'') to reduce tellurite to metallic tellurium. The tellurite reduction is colorimetrically indicated by brown colonies for most ''Cornyebacterium'' species or by a black halo around the ''C. diphtheriae'' colonies. The organism produces
catalase but not
urease
Ureases (), functionally, belong to the superfamily of amidohydrolases and phosphotriesterases. Ureases are found in numerous bacteria, fungi, algae, plants, and some invertebrates, as well as in soils, as a soil enzyme. They are nickel-contai ...
, which differentiates it from ''
Corynebacterium ulcerans
''Corynebacterium ulcerans'' is a rod-shaped, aerobic, and Gram-positive bacterium. Most ''Corynebacterium'' species are harmless, but some cause serious illness in humans, especially in immunocompromised humans. ''C. ulcerans'' has been known t ...
''. ''C. diphtheriae'' does not produce
pyrazinamidase PncA is a gene encoding pyrazinamidase in ''Mycobacterium'' species. Pyrazinamidase converts the drug pyrazinamide to the active form pyrazinoic acid
Pyrazinoic acid is a pyrazinamide metabolite. Possible role in tuberculosis treatment
Pyrazin ...
which differentiates from ''
Corynebacterium striatum
''Corynebacterium striatum'' is a bacterium that is a member of the Corynebacterium genus. It is classified as non- diphtheritic. The bacterium is a gram-positive prokaryote that assumes a 'club-like' morphology, more formally known as a coryne ...
'' and ''
Corynebacterium jeikeium
''Corynebacterium jeikeium'' is a rod-shaped, catalase-positive, aerobic species of Actinomycetota in the genus ''Corynebacterium''. ''C. jeikeium'' is pathogenic, typically causing an opportunistic infection seen most frequently in bone marrow ...
''.
Pathogenicity
![Dirty white pseudomembrane classically seen in diphtheria 2013-07-06 11-07](https://upload.wikimedia.org/wikipedia/commons/4/47/Dirty_white_pseudomembrane_classically_seen_in_diphtheria_2013-07-06_11-07.jpg)
''Corynebacterium diphtheriae'' is the bacterium that causes the disease called diphtheria.
Bacteriophages introduce a gene into the bacterial cells that makes a strain toxigenic. The strains that are not infected with these viruses are harmless.
''C. diphtheriae'' is a rod-shaped, Gram-positive, nonspore-forming, and nonmotile bacterium. C. diphtheriae has shown to exclusively infect humans. It is believed that humans may be the reservoir for this pathogen. However, there has been extremely rare cases in which ''C. diphtheriae'' has been found in animals. These infections were only toxigenic in 2 dogs and 2 horses.
The disease occurs primarily in tropical regions and
developing countries
A developing country is a sovereign state with a lesser developed industrial base and a lower Human Development Index (HDI) relative to other countries. However, this definition is not universally agreed upon. There is also no clear agreem ...
. Immunocompromised individuals, poorly immunized adults, and unvaccinated children are at the greatest risk for contracting diphtheria. Mode of transmission is person-to-person contact via respiratory droplets (i.e., coughing or sneezing). Less commonly, it could also be passed by touching open sores or contaminated surfaces. During the typical course of disease, the body region most commonly affected is the upper respiratory system. A thick, gray coating accumulates in the nasopharyngeal region, making breathing and swallowing more difficult. The disease remains contagious for at least two weeks following disappearance of symptoms, but has been known to last for up to a month.
The most common routes of entry for ''C. diphtheriae'' are the nose, tonsils, and throat. Individuals suffering from the disease may experience sore throat, weakness, fever, and swollen glands. This could cause even more dangerous symptoms such as shortness of breath.
If left untreated, diphtheria toxin may enter the bloodstream, causing damage to the kidneys, nerves, and heart. Extremely rare complications include suffocation and partial paralysis. A vaccine,
DTaP
The DPT vaccine or DTP vaccine is a class of combination vaccines against three infectious diseases in humans: diphtheria, pertussis (whooping cough), and tetanus. The vaccine components include diphtheria and tetanus toxoids and either kille ...
, effectively prevents the disease and is mandatory in the United States for participation in public education and some professions (exceptions apply).
The first step of ''C. diphtheriae'' infection involves the toxigenic bacteria colonizing a mucosal layer. In young children, this typically occurs in the upper respiratory tract mucosa. In adults, the infection is limited mostly to the tonsillar region. Some unusual sites of infection include the heart, larynx, trachea, bronchi, and anterior areas of the mouth including the buccal mucosa, the lips, tongue, and the hard and soft palate.
The bacteria have a number of virulence factors to help them localize on areas of the respiratory tract, many of which are yet to be fully understood as diphtheria does not affect many model hosts such as mice. One common virulence factor that has been studied ''in vitro'' is DIP0733, a multi-functional protein that has shown to have a role in bacterial adhesion to host cells and fibrogen-binding qualities. In experiments with mutant strains of the ''C. diphtheriae'', adhesion and epithelial infiltration decreased significantly. The ability to bind to extracellular matrices aids the bacteria in avoiding detection by the body's immune system.
The diphtheritic lesion is often covered by a pseudomembrane composed of fibrin, bacterial cells, 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 domain). 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.
Once the bacteria have localized in one area, they start multiplying and create the inflammatory pseudomembrane. Individuals with faucial diphtheria typically have the pseudomembrane grow over the tonsil and accessory structures, uvula, soft palate, and possibly the nasopharyngeal area. In upper respiratory tract diphtheria, the pseudomembrane can grow on the pharynx, larynx, trachea, and bronchi/bronchioles. The pseudomembrane starts off white in color and then later becomes dirty-gray and tough due to the necrotic epithelium.
Psuedomembrane formation on the trachea or bronchi will decrease efficiency of airflow. Over time, the diffusion rate in the alveoli decreases due to the lower airflow and decreases the partial pressure of oxygen in the systemic circulation, which can cause cyanosis and suffocation.
Transmission
Mode of transmission is person-to-person contact via respiratory droplets (i.e., coughing or sneezing), and less commonly, by touching open sores or contaminated surfaces.
Vaccine
A vaccine,
DTaP
The DPT vaccine or DTP vaccine is a class of combination vaccines against three infectious diseases in humans: diphtheria, pertussis (whooping cough), and tetanus. The vaccine components include diphtheria and tetanus toxoids and either kille ...
, effectively prevents the disease and is mandatory in the United States for participation in public education and some professions (exceptions apply).
The invention of the toxoid vaccine, which provides protection against ''Corynebacterium diphtheriae'', caused a dramatic shift on the bacterium’s rate of infection in the United States. Even though the vaccine was first made in the early 1800s, it did not become widely available until the early 1910s. According to the National Health and Nutrition Examination Survey (NHANES), “80 percent of persons age 12 to 19 years were immune to diphtheria” due to the wide use of the vaccine in the United States.
Diagnosis
Diagnosis of respiratory ''C. diphtheriae'' is made based on presentation clinically, whereas non-respiratory diphtheria may not be clinically suspected therefore laboratory testing is more reliant. Culturing is the most accurate kind of testing that will confirm or deny the prevalence of diphtheria toxins. The testing is done by swabbing the possibly infected area, as well as any lesions and sores.
Treatment and prevention
When a toxigenic strain of ''Corynebacterium diphtheriae'' infects the human body, it releases harmful toxins, especially to the throat.
Antitoxin
An antitoxin is an antibody with the ability to neutralize a specific toxin. Antitoxins are produced by certain animals, plants, and bacteria in response to toxin exposure. Although they are most effective in neutralizing toxins, they can also ...
s are used to prevent further harm. Antibiotics are also used to fight the infection. Typical antibiotics that are used against diphtheria involve penicillin or erythromycin. People infected with diphtheria must quarantine for at least 48 hours after being prescribed antibiotics. To confirm that the person is no longer contagious, tests are performed ensure that the bacteria have been cleared. People are then vaccinated prevent further transmission of the disease.
The wide-use of the diphtheria vaccine dramatically decreased the rate of infection and allows for primary prevention of the disease. Most people receive a 3-in-1 vaccine that consist of protection against diphtheria, tetanus and pertussis, which is commonly knowns as the DTaP or Tdap vaccine. DTaP vaccine is for children while the Tdap vaccine is known for adolescents and adults.
In the United States, the DTaP vaccine to parents of infants which typically involves a series of five shots is recommended. These vaccines are injected through the arm or thigh and are administered when the infant is 2 months, 4 months, 6 months, 15–18 months and then 4–6 years old.
[
Possible side events that are associated with the diphtheria vaccine include "mild fever, fussiness, drowsiness or tenderness at the injection site". Although it is rare, the DTaP vaccine may cause an allergic reaction that causes hives or a rash to breakout within minutes of administering the vaccine.][
]
Genetics
The genome of ''C. diphtheriae'' consists of a single circular chromosome of 2.5 Mbp, with no plasmid
A plasmid is a small, extrachromosomal DNA molecule within a cell that is physically separated from chromosomal DNA and can replicate independently. They are most commonly found as small circular, double-stranded DNA molecules in bacteria; how ...
s. Its genome shows an extreme compositional bias, being noticeably higher in G+C near the origin than at the terminus.
The Corynebacterium diphtheriae genome is a single circular chromosome that has no plasmids. These chromosomes have a high G+C content which is what contributes to their high genetic diversity. The high content of guanine and cytosine is not constant across the entire genome of the bacteria. There is a terminus of replication around the ~740kb region that causes a decrease in the G+C content. In other bacteria, it is often seen that the G+C content gets smaller near the terminus, but C. diphtheriae is a considerably strongly genome that has this occurrence. Chromosomal replication is one of the ways this happens within this genome.
Notes
References
See also
* Cutaneous diphtheria
* Diphtheria vaccine
Diphtheria vaccine is a toxoid vaccine against diphtheria, an illness caused by '' Corynebacterium diphtheriae''. Its use has resulted in a more than 90% decrease in number of cases globally between 1980 and 2000. The first dose is recommended ...
External links
CoryneRegNet
Database of Corynebacterial Transcription Factors and Regulatory Networks''
Corynebacterium diphtheriae genome
Type strain of ''Corynebacterium diphtheriae'' at Bac''Dive'' - the Bacterial Diversity Metadatabase
{{DEFAULTSORT:Corynebacterium Diphtheriae
Corynebacterium
Gram-positive bacteria
Diphtheria
Bacteria described in 1886
1884 in biology