Francisella tularensis is a
pathogenA pathogen , infectious agent, or germ, is a biological agent that causes disease or illness to its host....
ic species of
gram-negativeGram-negative bacteria are those bacteria that do not retain crystal violet dye in the Gram staining protocol. In a Gram stain test, a counterstain is added after the crystal violet, coloring all Gram-negative bacteria with a red or pink color...
bacteria and the causative agent of
tularemiaTularemia is a serious infectious disease caused by the bacterium Francisella tularensis. A gram-negative, non-motile coccobacillus, the bacterium has several subspecies with varying degrees of virulence. The most important of those is F...
or rabbit fever. It is a facultative
intracellularNot 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...
bacterium.
Due to its ease of spread by aerosol and its high
virulenceVirulence is the degree of pathogenicity of an organism: the relative ability of a pathogen to cause disease. The noun virulence derives from the adjective virulent. In discussing disease, the adjective virulent is used to describe effect severity, and in discussing pathogens, the degree of...
,
F. tularensis is classified as a
Class A agentIn United States law, select agents are pathogens or biological toxins which have been declared by the U.S. Department of Health and Human Services or by the U.S. Department of Agriculture to have the "potential to pose a severe threat to public health and safety"...
by the U.S. government.
This species was first identified in Tulare, CA between 1920-1925. Four subspecies (
biovarA biovar is a variant prokaryotic strain that differs physiologically and/or biochemically from other strains in a particular species. Morphovars are those strains that differ physiologically. Serovars are those strains that have antigenic properties that differ from other strains....
s) of
F.
Francisella tularensis is a
pathogenA pathogen , infectious agent, or germ, is a biological agent that causes disease or illness to its host....
ic species of
gram-negativeGram-negative bacteria are those bacteria that do not retain crystal violet dye in the Gram staining protocol. In a Gram stain test, a counterstain is added after the crystal violet, coloring all Gram-negative bacteria with a red or pink color...
bacteria and the causative agent of
tularemiaTularemia is a serious infectious disease caused by the bacterium Francisella tularensis. A gram-negative, non-motile coccobacillus, the bacterium has several subspecies with varying degrees of virulence. The most important of those is F...
or rabbit fever. It is a facultative
intracellularNot 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...
bacterium.
Due to its ease of spread by aerosol and its high
virulenceVirulence is the degree of pathogenicity of an organism: the relative ability of a pathogen to cause disease. The noun virulence derives from the adjective virulent. In discussing disease, the adjective virulent is used to describe effect severity, and in discussing pathogens, the degree of...
,
F. tularensis is classified as a
Class A agentIn United States law, select agents are pathogens or biological toxins which have been declared by the U.S. Department of Health and Human Services or by the U.S. Department of Agriculture to have the "potential to pose a severe threat to public health and safety"...
by the U.S. government.
Subspecies
This species was first identified in Tulare, CA between 1920-1925. Four subspecies (
biovarA biovar is a variant prokaryotic strain that differs physiologically and/or biochemically from other strains in a particular species. Morphovars are those strains that differ physiologically. Serovars are those strains that have antigenic properties that differ from other strains....
s) of
F. tularensis have been classified. The biovar
tularensis (or type A) is found predominantly in
North AmericaNorth America is the northern continent of the Americas, situated in the Earth's northern hemisphere and in the western hemisphere. It is bordered on the north by the Arctic Ocean, on the east by the North Atlantic Ocean, on the southeast by the Caribbean Sea, and on the west by the North Pacific...
and is the most virulent of the four known subspecies and is associated with lethal pulmomary infections. Biovar
palearctica (also known as biovar
holarctica or type B) is found predominantly in
EuropeEurope is, by convention, one of the world's seven continents. Comprising the westernmost peninsula of Eurasia, Europe is generally divided from Asia to its east by the water divide of the Ural Mountains, the Ural River, the Caspian Sea, the Caucasus Mountains , and the Black Sea to the southeast...
and
AsiaAsia is the world's largest and most populous continent, located in the eastern and northern hemispheres. It covers 8.6% of the earth's total surface area and with approximately 4 billion people, it hosts 60% of the world's current human population.Asia is traditionally defined as part of the...
but rarely leads to fatal disease. An attenuated live
vaccineA vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains a small amount of an agent that resembles a microorganism...
strain of subspecies
palearctica has been described, though it is not yet fully licensed by the
FDAThe Food and Drug Administration is a Government agency of the United States Department of Health and Human Services and is responsible for regulating and supervising the safety of foods, tobacco products, dietary supplements, Medication drugs, vaccines, Biopharmaceutical, blood transfusion,...
as a vaccine. Subspecies
novicida (previously classified as
F. novicida ) was characterized as a relatively nonvirulent strain; only two tularemia cases in North America have been attributed to
novicida and these were only in severely immunocompromised individuals. The fourth, biovar
mediasiatica, is found primarily in
central AsiaAsia is a region of Asia from the Caspian Sea in the west to central China in the east, and from southern Russia in the north to northern India in the south. It is also sometimes known as Middle Asia or Inner Asia, and is within the scope of the wider Eurasian continent.Various definitions of its...
; little is currently known about this subspecies or its ability to infect humans.
Pathogenesis
F. tularensis is capable of infecting a number of small mammals such as voles, rabbits, and muskrats, as well as humans. Despite this, no case of tularemia has been shown to be initiated by human-to-human transmission. Rather, tularemia is caused by contact with infected animals or vectors such as
tickTick is the common name for the small arachnids in superfamily Ixodoidea that, along with other mites, constitute the Acarina. Ticks are ectoparasites , living by hematophagy on the blood of mammals, birds, and occasionally reptiles and amphibians...
s,
mosquitoMosquito is a common insect in the family Culicidae...
s, and
deer fliesDeer flies are flies in the genus Chrysops of the family Tabanidae that can be pests to cattle, horses, and humans. A distinguishing characteristic of a deer fly is patterned gold or green eyes....
.
Infection with
F. tularensis can occur via several routes. The most common occurs via skin contact, yielding an
ulceroglandular form of the disease. Inhalation of bacteria - particularly biovar
tularensis, leads to the potentially lethal
pneumonicPneumonia is an inflammatory illness of the lung. Frequently, it is described as lung parenchyma/alveolar inflammation and abnormal alveolar filling with fluid ....
tularemia. While the pulmonary and ulceroglandular forms of tularemia are more common, other routes of inoculation have been described and include
oropharyngeal infection due to consumption of contaminated food and conjunctival infection due to inoculation at the eye.
F. tularensis is capable of surviving outside of a mammalian host for weeks at a time and has been found in water,
grasslandGrasslands are areas where the vegetation is dominated by grasses and other herbaceous plants . However, sedge and rush families can also be found. Grasslands occur naturally on all continents except Antarctica...
, and
haystackHaystack may refer to* Stacked hay* Haystack Observatory* Haystack, a research software project from MIT* Haystack Mountain Ski Area, a Vermont alpine ski area* Haystack Rock, a formation just off the coast at Cannon Beach, Oregon...
s. Aerosols containing the bacteria may be generated by disturbing carcasses due to brushcutting or lawn mowing; as a result, tularemia has been referred to as
lawnmower disease. Recent epidemiological studies have shown a positive correlation between occupations involving the above activities and infection with
F. tularensis.
Life Cycle
F. tularensis is a facultative intracellular bacterium that is capable of infecting most cell types but primarily infects macrophages in the host organism.
F. tularensis entry into the macrophage occurs via
phagocytosisPhagocytosis is the cellular process of phagocytes and protists of engulfing solid particles by the cell membrane to form an internal phagosome...
and the bacterium is sequestered from the interior of the infected cell by a
phagosomeIn cell biology, a phagosome is a vacuole formed around a particle absorbed by phagocytosis. The vacuole is formed by the fusion of the cell membrane around the particle. A phagosome is a cellular compartment in which pathogenic microorganisms can be killed and digested. Phagosomes fuse with...
.
F. tularensis then breaks out of this phagosome into the
cytosolThe cytosol or intracellular fluid is the liquid found inside cells. In eukaryotes this liquid is separated by cell membranes from the contents of the organelles suspended in the cytosol, such as the mitochondrial matrix inside the mitochondrion...
and rapidly proliferates. Eventually the infected cell undergoes
apoptosisApoptosis is the process of programmed cell death that may occur in multicellular organisms. Programmed cell death involves a series of biochemical events leading to a characteristic cell morphology and death; in more specific terms, a series of biochemical events that lead to a variety of...
, and the progeny bacteria are released to initiate new rounds of infection.
Virulence Factors
The virulence mechanisms for
F. tularensis have not been well characterized. Like other intracellular bacteria that break out of phagosomal compartments to replicate in the cytosol,
F. tularensis strains produce different hemolytic agents, which facilitate degradation of the phagosome. Specifically, a
hemolysinHemolysins are exotoxins produced by bacteria which cause lysis of red blood cells in vitro. Visualization of hemolysis of red blood cells in agar plates facilitates the categorization of some pathogenic bacteria such as Streptococcus...
protein NlyA with similarity to
Pseudomonas aeruginosaPseudomonas aeruginosa is a common bacterium which can cause disease in animals and humans. It is found in soil, water, skin flora and most man-made environments throughout the world. It thrives not only in normal atmospheres, but also with little oxygen, and has thus colonised many natural and...
HlyA was characterized in biovar
novicida whereas an acid phospholipase C AcpA has been found in other strains to act as a hemolysin.
While
F. tularensis does not contain virulence secretion systems typical of some better-characterized pathogenic bacteria, it does contain a number of
ATP binding cassetteATP-binding cassette transporters are members of a protein superfamily that is one of the largest and most ancient families with representatives in all extant phyla from prokaryotes to humans...
(ABC) proteins that may be linked to the secretion of virulence factors. In addition,
F. tularensis uses type IV
piliright|thumb|350px|Schematic drawing of bacterial conjugation. 1- Donor cell produces pilus. 2- Pilus attaches to recipient cell, brings the two cells together. 3- The mobile plasmid is nicked and a single strand of DNA is then transferred to the recipient cell...
to bind to the exterior of a host cell and thus become phagocytosed. Mutant strains lacking pili show severely attenuated pathogenicity.
The expression of a 23-kD protein known as IglC is required for
F. tularensis phagosomal breakout and intracellular replication; in its absence mutant
F. tularensis die and are degraded by the macrophage. This protein is located in a putative
pathogenicity islandPathogenicity islands are a distinct class of genomic islands which are acquired by horizontal transfer.They are incorporated in the genome of pathogenic microorganisms but are usually absent from those non-pathogenic organisms of the same or closely related species...
regulated by the transcription factor MglA.
F. tularensis,
in vitroA procedure performed in vitro is performed not in a living organism but in a controlled environment, such as in a test tube or Petri dish...
, downregulates the immune response of infected cells, a tactic used by a significant number of pathogenic organisms to ensure that replication is (albeit briefly) unhindered by the host
immune systemAn immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumour cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
by blocking the warning signals from the infected cells. This downmodulation of the immune response requires the IglC protein, though again it is not clear what the contributions of IglC and other genes are.
Several other putative virulence genes exist but have yet to be characterized for function in
F. tularensis pathogenicity.
Genetics
Like many other bacteria,
F. tularensis undergoes
asexualAsexual reproduction is reproduction which does not involve meiosis, ploidy reduction, or fertilization. Only one parent is involved in asexual reproduction. A more stringent definition is agamogenesis which refers to reproduction without the fusion of gametes...
replication. Bacteria will divide into two
daughter cellsCell division is a process by which a cell, called the parent cell, divides into two or more cells, called daughter cells. Cell division is usually a small segment of a larger cell cycle. This type of cell division in eukaryotes is known as mitosis, and leaves the daughter cell capable of dividing...
, each of which contains identical genetic information. Genetic variation may be introduced via
mutationIn biology, a mutation is a randomly derived change to the nucleotide sequence of the genetic material of an organism.Mutations can be caused by copying errors in the genetic material during cell division, or by exposure to mutagens , or can be induced by the organism itself, by cellular processes...
or
horizontal gene transferHorizontal gene transfer , also Lateral gene transfer , is any process in which an organism incorporates genetic material from another organism without being the offspring of that organism. By contrast, vertical transfer occurs when an organism receives genetic material from its ancestor, e.g...
.
The
genomeIn modern molecular biology the genome refers to all of its hereditary information encoded in DNA .The genome includes both the genes and the non-coding sequences of the DNA. The term was adapted in 1920 by Hans Winkler, Professor of Botany at the University of Hamburg, Germany...
of
F. tularensis biovar tularensis strain SCHU4 has been
sequencedA DNA sequence or genetic sequence is a succession of letters representing the primary structure of a real or hypothetical DNA molecule or strand, with the capacity to carry information as described by the central dogma of molecular biology....
. The studies resulting from the sequencing suggest that a number of gene coding regions in the
F. tularensis genome are disrupted by mutations and thus create blocks in a number of metabolic and synthetic pathways that are required for survival. This indicates that
F. tularensis has evolved to depend on the host organism for certain nutrients and other processes ordinarily taken care of by these disrupted genes.
The
F. tularensis genome contains unusual
transposonTransposons are sequences of DNA that can move around to different positions within the genome of a single cell, a process called transposition. In the process, they can cause mutations and change the amount of DNA in the genome. Transposons were also once called "jumping genes", and are examples...
-like elements resembling counterparts that normally are found in eukaryotic organisms.
Use as a biological weapon
When the U.S.
biological warfareBiological warfare , also known as germ warfare, is the use of pathogens such as viruses, bacteria, other disease-causing biological agents, or the toxins produced by them as biological weapons ....
program ended in 1969
F. tularensis was one of seven standardized biological weapons it had developed.
Genomics
- Francisella Genome Projects (from Genomes OnLine Database)
- Comparative Analysis of Francisella Genomes (at DOE's
The United States Department of Energy is a Cabinet-level department of the United States government concerned with the United States' policies regarding energy and safety in handling nuclear material...
IMG systemThe Integrated Microbial Genomes is a genome browsing and annotation system developed by the DOE-Joint Genome Institute. IMG contains all the draft and complete microbial genomes sequenced by the DOE-JGI integrated with other publicly available genomes...
)
External links