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Burkholderia mallei
Encyclopedia
Burkholderia mallei is a gram
-negative bipolar aerobic bacterium
, a Burkholderia
-genus human
and animal
pathogen
causing Glanders
; the Latin
name of this disease (malleus) gave name to the causative agent species. It is closely related to B. pseudomallei
, and by multilocus sequence typing
, it is a subspecies of B. pseudomallei. B. mallei evolved from B. pseudomallei by selective reduction and deletions from the B. pseudomallei genome. Unlike closely related Burkholderia pseudomallei
and other genus members, the bacterium is nonmotile; its shape is something in between a rod and a coccus
measuring some 1.5–3 μm in length and 0.5–1μm in diameter with rounded ends.
, it must cause disease in a host
mammal in order to live and to be transmitted from one host to another.
when compared to B. pseudomallei. B. malllei has about 1.4 Mb less DNA
than B. pseudomallei.There is speculation that B. mallei actually evolved from a strain of B. pseudomallei after the latter had infected an animal. The bacterium would have lost the genes that were not necessary for living in an animal host. This suggestion has found support from studies that compare strains of B. mallei to B. pseudomallei and indicate that their two respective genomes are very similar. The genes that allowed the bacterium to survive in a soil environment, like genes that gave B. mallei the capacity to protect against bacteriacidals antibiotic and antifungals, were likely deleted, thus the reason that B. mallei is not found outside of a host is because it lacks the genes that are necessary for survival in the soil. Genome comparisons also seem to indicate that the B. mallei is still evolving and adapting to an intracellular
lifestyle.
of 3.5 mega base pairs
(Mb) and a 2.3 MB "megaplasmid.” Many insertion sequences and phase-variable genes were also found.The genome for B. mallei is made up of two circular chromosomes. Chromosome 1 is where genes relating to metabolism
, capsule formation, and lipopolysaccharide
biosynthesis
are located. B. mallei has a polysaccharide
capsule which indicates its potential as a pathogen. Chromosome 2 is where most of the information regarding secretion systems and virulence
-associated genes are located. Multilocus sequence typing
has revealed that B. mallei most likely evolved from a B. pseudomallei clone
reduction. There are approximately 1000 B. pseudomellei genes absent or varying in the B. mallei genome. B. mallei’s genome also has a large amount of insertion sequences.
Burkholderia.
from the other include ribotyping
, pulsed-field gel electrophoresis
, multilocus enzyme electrophoresis, random amplified polymorphic DNA analysis
, and multilocus sequence typing. Comparing the DNA of B. mallei and B. pseudomallei must be done at the 23S rDNA level, however, since there is no identifiable difference between the two species at the 16S rDNA
level.
in a lab; nutrient agar
can be used to grow the bacteria. When grown in culture, B. mallei grows in smooth, grey translucent colonies
. In a period of 18 hours at 37°C, a B. mallei colony can grow to approximately 0.5 – 1 mm in diameter. A B. mallei culture will not grow on MacConkey agar
. Many microbiologists are unfamiliar with B. mallei and as a result it has frequently been misidentified as a Pseudomonas
species or as a contaminant in a culture.
, iodine
, mercuric chloride, potassium permanganate
, 1% sodium hypochlorite, and ethanol
. The microorganism can also be destroyed by heating or UV
. Antibiotic
s such as streptomycin
, amikacin
, tetracycline, doxycycline
, carbapenems, ceftazidime
, amoxicillin/clavulanic acid, piperacillin
, chloramphenicol
and sulfathiazole
have been reported to be effective against the bacteria in vitro
. B. mallei, like B. pseudomallei, is also resistant to a number of antibiotics including aminoglycoside
s, polymyxin
s, and beta-lactam
s. There is currently no vaccine
available for humans or animals to protect against B. mallei infection. An animal model that will predict immune responses necessary to create immunity
to the bacterium is needed before a vaccine can be developed. Mice are fairly close to humans in their susceptibility to B. mallei and would be the ideal choice of animal for creating a model for the vaccine.
disease, which historically affected animals, such as horse
s, mule
s, and donkey
s, the most and rarely affected humans. Horses are considered the natural host for B. mallei infection and are highly susceptible to it. B. mallei infects and gains access to the cell of its host through lysis
of the entry vacuole
. B. mallei has bacterial protein dependent actin-based motility once inside the cell. It is also able to initiate host cell fusion that results in multi-nucleated giant cells
(MNGCs). The consequence of MNGCs has yet to be determined, but it may allow the bacteria to spread to different cells, evade responses by the infected host’s immune system
, or allow the bacteria to remain in the host longer. B. mallei is able to survive inside host cells through its capabilities in disrupting the bacteria killing functions of the cell. It leaves the vacuoles early, which allows for efficient replication of the bacteria inside the cell. Leaving the cell early also keeps the bacteria from being destroyed by lysosomal defensins and other pathogen killing agents. MNGCs may help protect the bacteria from immune responses. B. mallei’s ability to live within the host cell makes developing a vaccine against it difficult and complex. The vaccine would need to create a cell-mediated immune response as well as a humoral
response to the bacteria in order to be effective in protecting against B. mallei. In regard to a vaccine against B. mallei, the closeness of B. mallei to B. pseudomallei may make it possible that a vaccine developed for either type of bacteria would be effective against the other.
infected with B. mallei and have Glanders
disease as a result, typically experience mucus
containing nasal discharge, lung lesions, and nodules
around the liver or spleen. Acute infection in horses results in a high fever, loss of fat or muscle, erosion of the surface of the nasal septum
, hemorrhaging
or mucus discharge. The bacterium mostly affects the lungs and airways.
Human infection with B. mallei is rare, although it occasionally occurs among lab workers dealing with the bacteria or those who are frequently near infected animals. The bacteria usually infect a person through their eyes, nose, mouth, or cuts in the skin. Once a person is infected with the bacteria, they develop a fever and rigors. Eventually they will get pneumonia
, pustules, and abscesses, which will prove fatal within a week to ten days if left untreated by antibiotics. The way someone is infected by the bacteria also affects the type of symptom
s that will result. If the bacteria enters through the skin, a local skin infection can result, while inhaling B. mallei can cause septicemic
or pulmonary infections of muscles, the liver, or spleen. B. mallei infection has a fatality rate of 95% if left untreated, and a 50% fatality rate in individuals treated with antibiotics.
, macrophages, and T cell
s go to the spleen in great quantities. The early cellular response to B. mallei infection involves Gr-1+ (antigen
) cells, and implies their importance to immunity against this bacterial infection. T cells (nitric oxide
) are actually more involved in combating B. mallei in the later stages of its infection of a host.
, Asia
, the Middle East
, Central America
, and South America
. Many Western countries were able to eliminate the disease through Glanders control programs and laws requiring notification of cases of infection to health departments and the destruction of any animal affected with B. mallei.
have a history of being on a list of potential biological warfare
agents. The Centers for Disease Control and Prevention
(CDC) classifies B. mallei as a Category B critical biological agent. As a result research regarding B. mallei may only be done in biosafety level
3 facilities in the US and internationally. Even though it is so highly infective and a potential biological weapon, little research has been conducted on this bacterium.
. The researcher had type 1 diabetes
and had been working with B. mallei for about two years, however, he did not always wear gloves while conducting his research. The researcher experienced enlargement of the lymph nodes and a fever
which lasted for 10 days even with antibiotic treatment. In the following weeks the researcher experienced fatigue, rigors, night sweats, and loss of weight. The next month, his symptoms seemed to disappear after treatment with clarithromycin
, but after the medication was stopped the symptoms reappeared. After conducting multiple tests on cultures from the researcher’s blood and a biopsied
portion of a liver abscess the bacteria was identified as B. mallei. Once it was established what the researcher was infected by, another course of antibiotics was given (imipenem
and doxycycline
) with 6 months of treatment. After a year the researcher made a full recovery.
This incident was the first case of a B. mallei infection in the United States since 1949. It also showed how a cut or skin abrasion is not absolutely necessary to contract the disease, as the researcher had no recollection of any cut or accident while working in the laboratory. The case was significant as it showed the difficulty that microbiology laboratories have in identifying bioweapon agents and the potential consequences if measures are not taken to prepare for an actual biological attack.
. The Germans used B. mallei to infect animals that were being sent from neutral countries to the Allies with Glanders. The Germans’ plans for biological warfare started in 1915 on the east coast of the United States; they intended to infect and kill the livestock that was being sent to the Allies and facilitate the transfer of the disease to humans. The east coast was where many animals were being assembled for shipment to the Allies fighting in Europe. The Germans also targeted Romania
, Norway
and Spain
’s animal supplies with cultures of Glanders. The German biological sabotage
eventually spread to Argentina
, where agents would rely on bacterial cultures from Spain to infect the cattle, horses, and mules that Argentina was supplying to the Allies. The Germans’ use of microbes as weapons is one of the only documented attacks of intentionally using biological weapons against neutral countries.
The Japanese used B. mallei in their biological warfare research units. The most notable and notorious unit, Unit 731
, used the bacterium to conduct experiments on live human subjects. However, the Japanese did not end up creating a biological weapon out of B. mallei. The Japanese did actually use B. mallei to test its effectiveness in contaminating water supplies, and the results of these tests were successful.
The Russians’ biological weapons program also took an interest in B. mallei and conducted field tests with it. Some of the researchers from the program were actually infected and killed by it during the course of their research. It has been suggested that the Russians eventually used B. mallei during their war in Afghanistan
against the mujahideen
.
Gram staining
Gram staining is a method of differentiating bacterial species into two large groups ....
-negative bipolar aerobic bacterium
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
, a Burkholderia
Burkholderia
Burkholderia is a genus of proteobacteria probably best known for its pathogenic members:Burkholderia mallei, responsible for glanders, a disease that occurs mostly in horses and related animals;...
-genus human
Human
Humans are the only living species in the Homo genus...
and animal
Animal
Animals are a major group of multicellular, eukaryotic organisms of the kingdom Animalia or Metazoa. Their body plan eventually becomes fixed as they develop, although some undergo a process of metamorphosis later on in their life. Most animals are motile, meaning they can move spontaneously and...
pathogen
Pathogen
A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...
causing Glanders
Glanders
Glanders is an infectious disease that occurs primarily in horses, mules, and donkeys. It can be contracted by other animals such as dogs, cats and goats...
; the Latin
Latin
Latin is an Italic language originally spoken in Latium and Ancient Rome. It, along with most European languages, is a descendant of the ancient Proto-Indo-European language. Although it is considered a dead language, a number of scholars and members of the Christian clergy speak it fluently, and...
name of this disease (malleus) gave name to the causative agent species. It is closely related to B. pseudomallei
Burkholderia pseudomallei
Burkholderia pseudomallei is a Gram-negative, bipolar, aerobic, motile rod-shaped bacterium. It infects humans and animals and causes the disease melioidosis. It is also capable of infecting plants....
, and by multilocus sequence typing
Multilocus sequence typing
Multilocus sequence typing is a technique in molecular biology for the typing of multiple loci. The procedure characterizes isolates of bacterial species using the DNA sequences of internal fragments of multiple housekeeping genes...
, it is a subspecies of B. pseudomallei. B. mallei evolved from B. pseudomallei by selective reduction and deletions from the B. pseudomallei genome. Unlike closely related Burkholderia pseudomallei
Burkholderia pseudomallei
Burkholderia pseudomallei is a Gram-negative, bipolar, aerobic, motile rod-shaped bacterium. It infects humans and animals and causes the disease melioidosis. It is also capable of infecting plants....
and other genus members, the bacterium is nonmotile; its shape is something in between a rod and a coccus
Coccus
Coccus can be used to describe any bacterium that has a spherical shape. It is one of the three distinct types of bacteria shapes, the other two being bacillus and spirillum cells...
measuring some 1.5–3 μm in length and 0.5–1μm in diameter with rounded ends.
Discovery and Early History
Wilhelm Schütz and Friedrich Löffler first isolated Burkholderia mallei in 1882. It was isolated from an infected liver and spleen of a horse. This bacterium is also one of the first to be identified containing a type VI secretion system which is important for its pathogenicity.Burkholderiaceae Family
Most organisms within the Burkholderiaceae Family live in soil, however, B. mallei does not. Because B. mallei is an obligate mammalian pathogenPathogen
A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...
, it must cause disease in a host
Host (biology)
In biology, a host is an organism that harbors a parasite, or a mutual or commensal symbiont, typically providing nourishment and shelter. In botany, a host plant is one that supplies food resources and substrate for certain insects or other fauna...
mammal in order to live and to be transmitted from one host to another.
Burkholderia Genus
B.mallei is very closely related to B. pseudomallei, being 99% identical in conserved genesGênes
Gênes is the name of a département of the First French Empire in present Italy, named after the city of Genoa. It was formed in 1805, when Napoleon Bonaparte occupied the Republic of Genoa. Its capital was Genoa, and it was divided in the arrondissements of Genoa, Bobbio, Novi Ligure, Tortona and...
when compared to B. pseudomallei. B. malllei has about 1.4 Mb less DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
than B. pseudomallei.There is speculation that B. mallei actually evolved from a strain of B. pseudomallei after the latter had infected an animal. The bacterium would have lost the genes that were not necessary for living in an animal host. This suggestion has found support from studies that compare strains of B. mallei to B. pseudomallei and indicate that their two respective genomes are very similar. The genes that allowed the bacterium to survive in a soil environment, like genes that gave B. mallei the capacity to protect against bacteriacidals antibiotic and antifungals, were likely deleted, thus the reason that B. mallei is not found outside of a host is because it lacks the genes that are necessary for survival in the soil. Genome comparisons also seem to indicate that the B. mallei is still evolving and adapting to an intracellular
Intracellular
Not to be confused with intercellular, meaning "between cells".In cell biology, molecular biology and related fields, the word intracellular means "inside the cell".It is used in contrast to extracellular...
lifestyle.
Genome
The genome of B. mallei was sequenced in the United States by The Institute of Genomic Research (TIGR). The size of the genome is smaller than that of the closely related B. pseudomallei. The B. mallei sequence revealed a chromosomeChromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
of 3.5 mega base pairs
Base pair
In molecular biology and genetics, the linking between two nitrogenous bases on opposite complementary DNA or certain types of RNA strands that are connected via hydrogen bonds is called a base pair...
(Mb) and a 2.3 MB "megaplasmid.” Many insertion sequences and phase-variable genes were also found.The genome for B. mallei is made up of two circular chromosomes. Chromosome 1 is where genes relating to metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
, capsule formation, and lipopolysaccharide
Lipopolysaccharide
Lipopolysaccharides , also known as lipoglycans, are large molecules consisting of a lipid and a polysaccharide joined by a covalent bond; they are found in the outer membrane of Gram-negative bacteria, act as endotoxins and elicit strong immune responses in animals.-Functions:LPS is the major...
biosynthesis
Biosynthesis
Biosynthesis is an enzyme-catalyzed process in cells of living organisms by which substrates are converted to more complex products. The biosynthesis process often consists of several enzymatic steps in which the product of one step is used as substrate in the following step...
are located. B. mallei has a polysaccharide
Polysaccharide
Polysaccharides are long carbohydrate molecules, of repeated monomer units joined together by glycosidic bonds. They range in structure from linear to highly branched. Polysaccharides are often quite heterogeneous, containing slight modifications of the repeating unit. Depending on the structure,...
capsule which indicates its potential as a pathogen. Chromosome 2 is where most of the information regarding secretion systems and virulence
Virulence
Virulence is by MeSH definition the degree of pathogenicity within a group or species of parasites as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. The pathogenicity of an organism - its ability to cause disease - is determined by its...
-associated genes are located. Multilocus sequence typing
Multilocus sequence typing
Multilocus sequence typing is a technique in molecular biology for the typing of multiple loci. The procedure characterizes isolates of bacterial species using the DNA sequences of internal fragments of multiple housekeeping genes...
has revealed that B. mallei most likely evolved from a B. pseudomallei clone
Clone (cell biology)
A clone is a group of identical cells that share a common ancestry, meaning they are derived from the same mother cell.Clonality implies the state of a cell or a substance being derived from one source or the other...
reduction. There are approximately 1000 B. pseudomellei genes absent or varying in the B. mallei genome. B. mallei’s genome also has a large amount of insertion sequences.
Taxonomy
Burkholderia mallei was first called “Bacillus mallei” and was in the genus Pseudomonas until the early 1990s. It has also been referred to as “farcy.” It is now part of the genusGenus
In biology, a genus is a low-level taxonomic rank used in the biological classification of living and fossil organisms, which is an example of definition by genus and differentia...
Burkholderia.
Typing
There is no standardized system for differentiating between B. mallei and B. pseudomallei. The methods that have been used to differentiate and identify one strainStrain (biology)
In biology, a strain is a low-level taxonomic rank used in three related ways.-Microbiology and virology:A strain is a genetic variant or subtype of a micro-organism . For example, a "flu strain" is a certain biological form of the influenza or "flu" virus...
from the other include ribotyping
Ribotyping
Ribotyping involves the fingerprinting of genomic DNA restriction fragments that contain all or part of the genes coding for the 16S and 23S rRNA. Conceptually, ribotyping is similar to probing restriction fragments of chromosomal DNA with cloned probes ....
, pulsed-field gel electrophoresis
Pulsed field gel electrophoresis
Pulsed field gel electrophoresis is a technique used for the separation of large deoxyribonucleic acid molecules by applying an electric field that periodically changes direction to a gel matrix.-Historical background:...
, multilocus enzyme electrophoresis, random amplified polymorphic DNA analysis
RAPD
RAPD stands for random amplification of polymorphic DNA. It is a type of PCR reaction, but the segments of DNA that are amplified are random. The scientist performing RAPD creates several arbitrary, short primers , then proceeds with the PCR using a large template of genomic DNA, hoping that...
, and multilocus sequence typing. Comparing the DNA of B. mallei and B. pseudomallei must be done at the 23S rDNA level, however, since there is no identifiable difference between the two species at the 16S rDNA
16S ribosomal RNA
16S ribosomal RNA is a component of the 30S subunit of prokaryotic ribosomes. It is approximately 1.5kb in length...
level.
Growth in Culture
Both B. mallei and B. pseudomallei can be culturedMicrobiological culture
A microbiological culture, or microbial culture, is a method of multiplying microbial organisms by letting them reproduce in predetermined culture media under controlled laboratory conditions. Microbial cultures are used to determine the type of organism, its abundance in the sample being tested,...
in a lab; nutrient agar
Nutrient agar
Nutrient agar is a microbiological growth medium commonly used for the routine cultivation of non-fastidious bacteria. It is useful because it remains solid even at relatively high temperatures. Also, bacteria grown in nutrient agar grows on the surface, and is clearly visible as small colonies...
can be used to grow the bacteria. When grown in culture, B. mallei grows in smooth, grey translucent colonies
Colony (biology)
In biology, a colony reference to several individual organisms of the same species living closely together, usually for mutual benefit, such as stronger defense or the ability to attack bigger prey. Some insects live only in colonies...
. In a period of 18 hours at 37°C, a B. mallei colony can grow to approximately 0.5 – 1 mm in diameter. A B. mallei culture will not grow on MacConkey agar
MacConkey agar
MacConkey agar is a culture medium designed to grow Gram-negative bacteria and stain them for lactose fermentation.-Contents:It contains bile salts MacConkey agar is a culture medium designed to grow Gram-negative bacteria and stain them for lactose fermentation.-Contents:It contains bile salts...
. Many microbiologists are unfamiliar with B. mallei and as a result it has frequently been misidentified as a Pseudomonas
Pseudomonas
Pseudomonas is a genus of gammaproteobacteria, belonging to the family Pseudomonadaceae containing 191 validly described species.Recently, 16S rRNA sequence analysis has redefined the taxonomy of many bacterial species. As a result, the genus Pseudomonas includes strains formerly classified in the...
species or as a contaminant in a culture.
Antibiotic Resistance and Susceptibility
The bacterium is susceptible to numerous disinfectants including benzalkonium chlorideBenzalkonium chloride
Benzalkonium chloride, also known as alkyldimethylbenzylammonium chloride and ADBAC, is a mixture of alkylbenzyldimethylammonium chlorides of various even-numbered alkyl chain lengths. This product is a nitrogenous cationic surface-acting agent belonging to the quaternary ammonium group...
, iodine
Iodine
Iodine is a chemical element with the symbol I and atomic number 53. The name is pronounced , , or . The name is from the , meaning violet or purple, due to the color of elemental iodine vapor....
, mercuric chloride, potassium permanganate
Potassium permanganate
Potassium permanganate is an inorganic chemical compound with the formula KMnO4. It is a salt consisting of K+ and MnO4− ions. Formerly known as permanganate of potash or Condy's crystals, it is a strong oxidizing agent. It dissolves in water to give intensely purple solutions, the...
, 1% sodium hypochlorite, and ethanol
Ethanol
Ethanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...
. The microorganism can also be destroyed by heating or UV
Ultraviolet
Ultraviolet light is electromagnetic radiation with a wavelength shorter than that of visible light, but longer than X-rays, in the range 10 nm to 400 nm, and energies from 3 eV to 124 eV...
. Antibiotic
Antibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...
s such as streptomycin
Streptomycin
Streptomycin is an antibiotic drug, the first of a class of drugs called aminoglycosides to be discovered, and was the first antibiotic remedy for tuberculosis. It is derived from the actinobacterium Streptomyces griseus. Streptomycin is a bactericidal antibiotic. Streptomycin cannot be given...
, amikacin
Amikacin
Amikacin is an aminoglycoside antibiotic used to treat different types of bacterial infections. Amikacin works by binding to the bacterial 30S ribosomal subunit, causing misreading of mRNA and leaving the bacterium unable to synthesize proteins vital to its growth.-Administration:Amikacin may be...
, tetracycline, doxycycline
Doxycycline
Doxycycline INN is a member of the tetracycline antibiotics group, and is commonly used to treat a variety of infections. Doxycycline is a semisynthetic tetracycline invented and clinically developed in the early 1960s by Pfizer Inc. and marketed under the brand name Vibramycin. Vibramycin...
, carbapenems, ceftazidime
Ceftazidime
Ceftazidime is a third-generation cephalosporin antibiotic. Like other third-generation cephalosporins, it has broad spectrum activity against Gram-positive and Gram-negative bacteria. Unlike most third-generation agents, it is active against Pseudomonas aeruginosa, however it has weaker activity...
, amoxicillin/clavulanic acid, piperacillin
Piperacillin
Piperacillin is an extended spectrum beta-lactam antibiotic of the ureidopenicillin class.It is normally used together with a beta-lactamase inhibitor such as tazobactam. The combination drug piperacillin/tazobactam is commercially available as e.g. Tazocin, Zosyn, Brodactam, Piptaz and as Trezora...
, chloramphenicol
Chloramphenicol
Chloramphenicol is a bacteriostatic antimicrobial that became available in 1949. It is considered a prototypical broad-spectrum antibiotic, alongside the tetracyclines, and as it is both cheap and easy to manufacture it is frequently found as a drug of choice in the third world.Chloramphenicol is...
and sulfathiazole
Sulfathiazole
Sulfathiazole is an organosulfur compound that has been used as a short-acting sulfa drug. It once was a common oral and topical antimicrobial until less toxic alternatives were discovered. It is still occasionally used, sometimes in combination with sulfabenzamide and sulfacetamide, and in...
have been reported to be effective against the bacteria in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
. B. mallei, like B. pseudomallei, is also resistant to a number of antibiotics including aminoglycoside
Aminoglycoside
An aminoglycoside is a molecule or a portion of a molecule composed of amino-modifiedsugars.Several aminoglycosides function as antibiotics that are effective against certain types of bacteria...
s, polymyxin
Polymyxin
Polymyxins are antibiotics, with a general structure consisting of a cyclicpeptide with a long hydrophobic tail. They disrupt the structure of thebacterial cell membrane by interacting with its phospholipids...
s, and beta-lactam
Beta-lactam
A β-lactam ring, is a four-membered lactam. It is named as such, because the nitrogen atom is attached to the β-carbon relative to the carbonyl...
s. There is currently no vaccine
Vaccine
A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism, and is often made from weakened or killed forms of the microbe or its toxins...
available for humans or animals to protect against B. mallei infection. An animal model that will predict immune responses necessary to create immunity
Immunity (medical)
Immunity is a biological term that describes a state of having sufficient biological defenses to avoid infection, disease, or other unwanted biological invasion. Immunity involves both specific and non-specific components. The non-specific components act either as barriers or as eliminators of wide...
to the bacterium is needed before a vaccine can be developed. Mice are fairly close to humans in their susceptibility to B. mallei and would be the ideal choice of animal for creating a model for the vaccine.
Pathogenicity
B. mallei is responsible for causing GlandersGlanders
Glanders is an infectious disease that occurs primarily in horses, mules, and donkeys. It can be contracted by other animals such as dogs, cats and goats...
disease, which historically affected animals, such as horse
Horse
The horse is one of two extant subspecies of Equus ferus, or the wild horse. It is a single-hooved mammal belonging to the taxonomic family Equidae. The horse has evolved over the past 45 to 55 million years from a small multi-toed creature into the large, single-toed animal of today...
s, mule
Mule
A mule is the offspring of a male donkey and a female horse. Horses and donkeys are different species, with different numbers of chromosomes. Of the two F1 hybrids between these two species, a mule is easier to obtain than a hinny...
s, and donkey
Donkey
The donkey or ass, Equus africanus asinus, is a domesticated member of the Equidae or horse family. The wild ancestor of the donkey is the African Wild Ass, E...
s, the most and rarely affected humans. Horses are considered the natural host for B. mallei infection and are highly susceptible to it. B. mallei infects and gains access to the cell of its host through lysis
Lysis
Lysis refers to the breaking down of a cell, often by viral, enzymic, or osmotic mechanisms that compromise its integrity. A fluid containing the contents of lysed cells is called a "lysate"....
of the entry vacuole
Vacuole
A vacuole is a membrane-bound organelle which is present in all plant and fungal cells and some protist, animal and bacterial cells. Vacuoles are essentially enclosed compartments which are filled with water containing inorganic and organic molecules including enzymes in solution, though in certain...
. B. mallei has bacterial protein dependent actin-based motility once inside the cell. It is also able to initiate host cell fusion that results in multi-nucleated giant cells
Giant cell
A giant cell is a mass formed by the union of several distinct cells . It can arise in response to an infection or foreign body.Types include:* foreign-body giant cell* Langhans giant cell* Touton giant cells...
(MNGCs). The consequence of MNGCs has yet to be determined, but it may allow the bacteria to spread to different cells, evade responses by the infected host’s immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
, or allow the bacteria to remain in the host longer. B. mallei is able to survive inside host cells through its capabilities in disrupting the bacteria killing functions of the cell. It leaves the vacuoles early, which allows for efficient replication of the bacteria inside the cell. Leaving the cell early also keeps the bacteria from being destroyed by lysosomal defensins and other pathogen killing agents. MNGCs may help protect the bacteria from immune responses. B. mallei’s ability to live within the host cell makes developing a vaccine against it difficult and complex. The vaccine would need to create a cell-mediated immune response as well as a humoral
Humoral immunity
The Humoral Immune Response is the aspect of immunity that is mediated by secreted antibodies produced in the cells of the B lymphocyte lineage . B Cells transform into plasma cells which secrete antibodies...
response to the bacteria in order to be effective in protecting against B. mallei. In regard to a vaccine against B. mallei, the closeness of B. mallei to B. pseudomallei may make it possible that a vaccine developed for either type of bacteria would be effective against the other.
Symptoms of B. mallei Infection
Horses who are chronicallyChronic (medicine)
A chronic disease is a disease or other human health condition that is persistent or long-lasting in nature. The term chronic is usually applied when the course of the disease lasts for more than three months. Common chronic diseases include asthma, cancer, diabetes and HIV/AIDS.In medicine, the...
infected with B. mallei and have Glanders
Glanders
Glanders is an infectious disease that occurs primarily in horses, mules, and donkeys. It can be contracted by other animals such as dogs, cats and goats...
disease as a result, typically experience mucus
Mucus
In vertebrates, mucus is a slippery secretion produced by, and covering, mucous membranes. Mucous fluid is typically produced from mucous cells found in mucous glands. Mucous cells secrete products that are rich in glycoproteins and water. Mucous fluid may also originate from mixed glands, which...
containing nasal discharge, lung lesions, and nodules
Nodule (medicine)
For use of the term nodule in dermatology, see Nodule In medicine, a nodule refers to a relatively hard, roughly spherical abnormal structure....
around the liver or spleen. Acute infection in horses results in a high fever, loss of fat or muscle, erosion of the surface of the nasal septum
Nasal septum
The nasal septum separates the left and right airways in the nose, dividing the two nostrils.It is depressed by the Depressor septi nasi muscle.-Composition:The fleshy external end of the nasal septum is sometimes also called columella....
, hemorrhaging
Bleeding
Bleeding, technically known as hemorrhaging or haemorrhaging is the loss of blood or blood escape from the circulatory system...
or mucus discharge. The bacterium mostly affects the lungs and airways.
Human infection with B. mallei is rare, although it occasionally occurs among lab workers dealing with the bacteria or those who are frequently near infected animals. The bacteria usually infect a person through their eyes, nose, mouth, or cuts in the skin. Once a person is infected with the bacteria, they develop a fever and rigors. Eventually they will get pneumonia
Pneumonia
Pneumonia is an inflammatory condition of the lung—especially affecting the microscopic air sacs —associated with fever, chest symptoms, and a lack of air space on a chest X-ray. Pneumonia is typically caused by an infection but there are a number of other causes...
, pustules, and abscesses, which will prove fatal within a week to ten days if left untreated by antibiotics. The way someone is infected by the bacteria also affects the type of symptom
Symptom
A symptom is a departure from normal function or feeling which is noticed by a patient, indicating the presence of disease or abnormality...
s that will result. If the bacteria enters through the skin, a local skin infection can result, while inhaling B. mallei can cause septicemic
Sepsis
Sepsis is a potentially deadly medical condition that is characterized by a whole-body inflammatory state and the presence of a known or suspected infection. The body may develop this inflammatory response by the immune system to microbes in the blood, urine, lungs, skin, or other tissues...
or pulmonary infections of muscles, the liver, or spleen. B. mallei infection has a fatality rate of 95% if left untreated, and a 50% fatality rate in individuals treated with antibiotics.
Cellular Response to Infection
In the first days of B. mallei infection neutrophilsNeutrophil granulocyte
Neutrophil granulocytes are the most abundant type of white blood cells in mammals and form an essential part of the innate immune system. They are generally referred to as either neutrophils or polymorphonuclear neutrophils , and are subdivided into segmented neutrophils and banded neutrophils...
, macrophages, and T cell
T cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
s go to the spleen in great quantities. The early cellular response to B. mallei infection involves Gr-1+ (antigen
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
) cells, and implies their importance to immunity against this bacterial infection. T cells (nitric oxide
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...
) are actually more involved in combating B. mallei in the later stages of its infection of a host.
Global Presence
B. mallei has been eradicated in the United States and most Western countries, but still affects animals in AfricaAfrica
Africa is the world's second largest and second most populous continent, after Asia. At about 30.2 million km² including adjacent islands, it covers 6% of the Earth's total surface area and 20.4% of the total land area...
, Asia
Asia
Asia is the world's largest and most populous continent, located primarily in the eastern and northern hemispheres. It covers 8.7% of the Earth's total surface area and with approximately 3.879 billion people, it hosts 60% of the world's current human population...
, the Middle East
Middle East
The Middle East is a region that encompasses Western Asia and Northern Africa. It is often used as a synonym for Near East, in opposition to Far East...
, Central America
Central America
Central America is the central geographic region of the Americas. It is the southernmost, isthmian portion of the North American continent, which connects with South America on the southeast. When considered part of the unified continental model, it is considered a subcontinent...
, and South America
South America
South America is a continent situated in the Western Hemisphere, mostly in the Southern Hemisphere, with a relatively small portion in the Northern Hemisphere. The continent is also considered a subcontinent of the Americas. It is bordered on the west by the Pacific Ocean and on the north and east...
. Many Western countries were able to eliminate the disease through Glanders control programs and laws requiring notification of cases of infection to health departments and the destruction of any animal affected with B. mallei.
Potential as a Biological Weapon
B. mallei as well as B. pseudomalleiBurkholderia pseudomallei
Burkholderia pseudomallei is a Gram-negative, bipolar, aerobic, motile rod-shaped bacterium. It infects humans and animals and causes the disease melioidosis. It is also capable of infecting plants....
have a history of being on a list of potential biological warfare
Biological warfare
Biological warfare is the use of biological toxins or infectious agents such as bacteria, viruses, and fungi with intent to kill or incapacitate humans, animals or plants as an act of war...
agents. The Centers for Disease Control and Prevention
Centers for Disease Control and Prevention
The Centers for Disease Control and Prevention are a United States federal agency under the Department of Health and Human Services headquartered in Druid Hills, unincorporated DeKalb County, Georgia, in Greater Atlanta...
(CDC) classifies B. mallei as a Category B critical biological agent. As a result research regarding B. mallei may only be done in biosafety level
Biosafety level
A biosafety level is the level of the biocontainment precautions required to isolate dangerous biological agents in an enclosed facility. The levels of containment range from the lowest biosafety level 1 to the highest at level 4 . In the United States, the Centers for Disease Control and...
3 facilities in the US and internationally. Even though it is so highly infective and a potential biological weapon, little research has been conducted on this bacterium.
Incidence in the United States
In March 2000, one of the first cases since the 1940s of Glanders in the United States occurred in a young microbiologist working for the U.S. Army Medical Research Institute for Infectious DiseasesUnited States Army Medical Research Institute of Infectious Diseases
The U.S. Army Medical Research Institute of Infectious Diseases is the U.S Army’s main institution and facility for defensive research into countermeasures against biological warfare. It is located on Fort Detrick, Maryland and is a subordinate lab of the U. S...
. The researcher had type 1 diabetes
Diabetes mellitus type 1
Diabetes mellitus type 1 is a form of diabetes mellitus that results from autoimmune destruction of insulin-producing beta cells of the pancreas. The subsequent lack of insulin leads to increased blood and urine glucose...
and had been working with B. mallei for about two years, however, he did not always wear gloves while conducting his research. The researcher experienced enlargement of the lymph nodes and a fever
Fever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...
which lasted for 10 days even with antibiotic treatment. In the following weeks the researcher experienced fatigue, rigors, night sweats, and loss of weight. The next month, his symptoms seemed to disappear after treatment with clarithromycin
Clarithromycin
Clarithromycin is a macrolide antibiotic used to treat pharyngitis, tonsillitis, acute maxillary sinusitis, acute bacterial exacerbation of chronic bronchitis, pneumonia , skin and skin structure infections...
, but after the medication was stopped the symptoms reappeared. After conducting multiple tests on cultures from the researcher’s blood and a biopsied
Biopsy
A biopsy is a medical test involving sampling of cells or tissues for examination. It is the medical removal of tissue from a living subject to determine the presence or extent of a disease. The tissue is generally examined under a microscope by a pathologist, and can also be analyzed chemically...
portion of a liver abscess the bacteria was identified as B. mallei. Once it was established what the researcher was infected by, another course of antibiotics was given (imipenem
Imipenem
Imipenem is an intravenous β-lactam antibiotic developed in 1980. It has an extremely broad spectrum of activity.Imipenem belongs to the subgroup of carbapenems. It is derived from a compound called thienamycin, which is produced by the bacterium Streptomyces cattleya...
and doxycycline
Doxycycline
Doxycycline INN is a member of the tetracycline antibiotics group, and is commonly used to treat a variety of infections. Doxycycline is a semisynthetic tetracycline invented and clinically developed in the early 1960s by Pfizer Inc. and marketed under the brand name Vibramycin. Vibramycin...
) with 6 months of treatment. After a year the researcher made a full recovery.
This incident was the first case of a B. mallei infection in the United States since 1949. It also showed how a cut or skin abrasion is not absolutely necessary to contract the disease, as the researcher had no recollection of any cut or accident while working in the laboratory. The case was significant as it showed the difficulty that microbiology laboratories have in identifying bioweapon agents and the potential consequences if measures are not taken to prepare for an actual biological attack.
History as a Weapon of Biological Warfare
B. mallei was intentionally used to infect animals and humans during World War IWorld War I
World War I , which was predominantly called the World War or the Great War from its occurrence until 1939, and the First World War or World War I thereafter, was a major war centred in Europe that began on 28 July 1914 and lasted until 11 November 1918...
. The Germans used B. mallei to infect animals that were being sent from neutral countries to the Allies with Glanders. The Germans’ plans for biological warfare started in 1915 on the east coast of the United States; they intended to infect and kill the livestock that was being sent to the Allies and facilitate the transfer of the disease to humans. The east coast was where many animals were being assembled for shipment to the Allies fighting in Europe. The Germans also targeted Romania
Romania
Romania is a country located at the crossroads of Central and Southeastern Europe, on the Lower Danube, within and outside the Carpathian arch, bordering on the Black Sea...
, Norway
Norway
Norway , officially the Kingdom of Norway, is a Nordic unitary constitutional monarchy whose territory comprises the western portion of the Scandinavian Peninsula, Jan Mayen, and the Arctic archipelago of Svalbard and Bouvet Island. Norway has a total area of and a population of about 4.9 million...
and Spain
Spain
Spain , officially the Kingdom of Spain languages]] under the European Charter for Regional or Minority Languages. In each of these, Spain's official name is as follows:;;;;;;), is a country and member state of the European Union located in southwestern Europe on the Iberian Peninsula...
’s animal supplies with cultures of Glanders. The German biological sabotage
Sabotage
Sabotage is a deliberate action aimed at weakening another entity through subversion, obstruction, disruption, or destruction. In a workplace setting, sabotage is the conscious withdrawal of efficiency generally directed at causing some change in workplace conditions. One who engages in sabotage is...
eventually spread to Argentina
Argentina
Argentina , officially the Argentine Republic , is the second largest country in South America by land area, after Brazil. It is constituted as a federation of 23 provinces and an autonomous city, Buenos Aires...
, where agents would rely on bacterial cultures from Spain to infect the cattle, horses, and mules that Argentina was supplying to the Allies. The Germans’ use of microbes as weapons is one of the only documented attacks of intentionally using biological weapons against neutral countries.
The Japanese used B. mallei in their biological warfare research units. The most notable and notorious unit, Unit 731
Unit 731
was a covert biological and chemical warfare research and development unit of the Imperial Japanese Army that undertook lethal human experimentation during the Second Sino-Japanese War and World War II. It was responsible for some of the most notorious war crimes carried out by Japanese...
, used the bacterium to conduct experiments on live human subjects. However, the Japanese did not end up creating a biological weapon out of B. mallei. The Japanese did actually use B. mallei to test its effectiveness in contaminating water supplies, and the results of these tests were successful.
The Russians’ biological weapons program also took an interest in B. mallei and conducted field tests with it. Some of the researchers from the program were actually infected and killed by it during the course of their research. It has been suggested that the Russians eventually used B. mallei during their war in Afghanistan
Afghanistan
Afghanistan , officially the Islamic Republic of Afghanistan, is a landlocked country located in the centre of Asia, forming South Asia, Central Asia and the Middle East. With a population of about 29 million, it has an area of , making it the 42nd most populous and 41st largest nation in the world...
against the mujahideen
Mujahideen
Mujahideen are Muslims who struggle in the path of God. The word is from the same Arabic triliteral as jihad .Mujahideen is also transliterated from Arabic as mujahedin, mujahedeen, mudžahedin, mudžahidin, mujahidīn, mujaheddīn and more.-Origin of the concept:The beginnings of Jihad are traced...
.
External links
- Burkholderia mallei genomes and related information at PATRIC, a Bioinformatics Resource Center funded by NIAID
- Pathema-Burkholderia Resource
- Centers for Disease Control and Prevention: Glanders (Burkholderia mallei) General Information
- Centers for Disease Control and Prevention: Bioterrorism Agents/Diseases
- Center for Biosecurity