Francisella tularensis
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''Francisella tularensis'' is a
pathogen In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a germ ...
ic species of
Gram-negative Gram-negative bacteria are bacteria that do not retain the crystal violet stain used in the Gram staining method of bacterial differentiation. They are characterized by their cell envelopes, which are composed of a thin peptidoglycan cell wall ...
coccobacillus A coccobacillus (plural coccobacilli), or bacilluscocco, is a type of bacterium with a shape intermediate between cocci (spherical bacteria) and bacilli (rod-shaped bacteria). Coccobacilli, then, are very short rods which may be mistaken for coc ...
, an
aerobic Aerobic means "requiring air," in which "air" usually means oxygen. Aerobic may also refer to * Aerobic exercise, prolonged exercise of moderate intensity * Aerobics, a form of aerobic exercise * Aerobic respiration, the aerobic process of cel ...
bacterium Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among ...
. It is nonspore-forming, nonmotile, and the causative agent of
tularemia Tularemia, also known as rabbit fever, is an infectious disease caused by the bacterium ''Francisella tularensis''. Symptoms may include fever, skin ulcers, and enlarged lymph nodes. Occasionally, a form that results in pneumonia or a throat infe ...
, the pneumonic form of which is often lethal without treatment. It is a fastidious, facultative
intracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...
bacterium, which requires
cysteine Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile. When present as a deprotonated catalytic residue, sometime ...
for growth. Due to its low infectious dose, ease of spread by aerosol, and high
virulence Virulence is a pathogen's or microorganism's ability to cause damage to a host. In most, especially in animal systems, virulence refers to the degree of damage caused by a microbe to its host. The pathogenicity of an organism—its ability to ca ...
, ''F. tularensis'' is classified as a Tier 1
Select Agent Under United States law, Biological select agents or toxins (BSATs) — or simply select agents for short — are bio-agents which (since 1997) have been declared by the U.S. Department of Health and Human Services (HHS) or by the U.S. Departme ...
by the U.S. government, along with other potential agents of bioterrorism such as ''
Yersinia pestis ''Yersinia pestis'' (''Y. pestis''; formerly '' Pasteurella pestis'') is a gram-negative, non-motile, coccobacillus bacterium without spores that is related to both ''Yersinia pseudotuberculosis'' and ''Yersinia enterocolitica''. It is a facult ...
,
Bacillus anthracis ''Bacillus anthracis'' is a gram-positive and rod-shaped bacterium that causes anthrax, a deadly disease to livestock and, occasionally, to humans. It is the only permanent ( obligate) pathogen within the genus ''Bacillus''. Its infection is a ...
'', and
Ebola Ebola, also known as Ebola virus disease (EVD) and Ebola hemorrhagic fever (EHF), is a viral hemorrhagic fever in humans and other primates, caused by ebolaviruses. Symptoms typically start anywhere between two days and three weeks after becom ...
virus. When found in nature, ''Francisella tularensis'' can survive for several weeks at low temperatures in animal carcasses, soil, and water. In the laboratory, ''F. tularensis'' appears as small rods (0.2 by 0.2 µm), and is grown best at 35–37 °C.


History

This species was discovered in ground squirrels in
Tulare County, California Tulare County ( ) is a County (United States), county located in the U.S. state of California. As of the 2010 United States Census, 2020 census, the population was 473,117. The county seat is Visalia, California, Visalia. The county is named for ...
in 1911. ''Bacterium tularense'' was soon isolated by
George Walter McCoy George Walter McCoy (1876–1952) was an American physician. An international expert on leprosy, he served as director of the National Institute of Health for more than twenty years. Early life and education McCoy was born in 1876 in the C ...
(1876–1952) of the US Plague Lab in San Francisco and reported in 1912. In 1922, Edward Francis (1872–1957), a physician and medical researcher from Ohio, discovered that ''Bacterium tularense'' was the causative agent of
tularemia Tularemia, also known as rabbit fever, is an infectious disease caused by the bacterium ''Francisella tularensis''. Symptoms may include fever, skin ulcers, and enlarged lymph nodes. Occasionally, a form that results in pneumonia or a throat infe ...
, after studying several cases with symptoms of the disease. Later, it became known as ''Francisella tularensis'', in honor of the discovery by Francis. The disease was also described in the
Fukushima may refer to: Japan * Fukushima Prefecture, Japanese prefecture ** Fukushima, Fukushima, capital city of Fukushima Prefecture, Japan ***Fukushima University, national university in Japan *** Fukushima Station (Fukushima) in Fukushima, Fukushim ...
region of Japan by Hachiro Ohara in the 1920s, where it was associated with hunting rabbits. In 1938, Soviet bacteriologist Vladimir Dorofeev (1911–1988) and his team recreated the infectious cycle of the pathogen in humans, and his team was the first to create protection measures. In 1947, Dorofeev independently isolated the pathogen that Francis discovered in 1922. Hence it is commonly known as ''Francisella dorofeev'' in former Soviet countries.


Classification

Three subspecies (
biovar A biovar is a variant prokaryotic strain that differs physiologically or biochemically from other strains in a particular species. Morphovars (or morphotypes) are those strains that differ morphologically. Serovars (or serotypes) are those strain ...
s) of ''F. tularensis'' are recognised (as of 2020):Sam R. Telford III, Heidi K. Goethert (2020). "Ecology of ''Francisella tularensis''", ''
Annual Review of Entomology The ''Annual Review of Entomology'' is a peer-reviewed academic journal that publishes review articles about entomology, the study of insects. First published in 1956 from a collaboration between the Entomological Society of America and Annual R ...
'' 65: 351–372
# ''F. t. tularensis'' (or type A), found predominantly in
North America North America is a continent in the Northern Hemisphere and almost entirely within the Western Hemisphere. It is bordered to the north by the Arctic Ocean, to the east by the Atlantic Ocean, to the southeast by South America and the Car ...
, is the most virulent of the four known subspecies, and is associated with lethal pulmonary infections. This includes the primary type A laboratory strain, SCHUS4. # ''F. t. holarctica'' (also known as biovar ''F. t. palearctica'' or type B) is found predominantly in
Europe Europe is a large peninsula conventionally considered a continent in its own right because of its great physical size and the weight of its history and traditions. Europe is also considered a Continent#Subcontinents, subcontinent of Eurasia ...
and
Asia Asia (, ) is one of the world's most notable geographical regions, which is either considered a continent in its own right or a subcontinent of Eurasia, which shares the continental landmass of Afro-Eurasia with Africa. Asia covers an area ...
, but rarely leads to fatal disease. An attenuated live
vaccine A vaccine is a biological Dosage form, preparation that provides active acquired immunity to a particular infectious disease, infectious or cancer, malignant disease. The safety and effectiveness of vaccines has been widely studied and verifie ...
strain of subspecies ''F. t. holarctica'' has been described, though it is not yet fully licensed by the
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
as a vaccine. This subspecies lacks the citrulline ureidase activity and ability to produce acid from glucose of biovar ''F. t. palearctica''. #''F. t. mediasiatica'', is found primarily in
central Asia Central Asia, also known as Middle Asia, is a subregion, region of Asia that stretches from the Caspian Sea in the west to western China and Mongolia in the east, and from Afghanistan and Iran in the south to Russia in the north. It includes t ...
; little is currently known about this subspecies or its ability to infect humans. Additionally, '' F. novicida'' has sometimes previously been classified as ''F. t. novicida''. It was characterized as a relatively nonvirulent ''Francisella''; only two tularemia cases in North America have been attributed to the organism, and these were only in severely
immunocompromised Immunodeficiency, also known as immunocompromisation, is a state in which the immune system's ability to fight infectious diseases and cancer is compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic factors that a ...
individuals.


Pathogenesis

''F. tularensis'' has been reported in
invertebrates Invertebrates are a paraphyletic group of animals that neither possess nor develop a vertebral column (commonly known as a ''backbone'' or ''spine''), derived from the notochord. This is a grouping including all animals apart from the chordate ...
including
insect Insects (from Latin ') are pancrustacean hexapod invertebrates of the class Insecta. They are the largest group within the arthropod phylum. Insects have a chitinous exoskeleton, a three-part body ( head, thorax and abdomen), three pairs ...
s and
tick Ticks (order Ixodida) are parasitic arachnids that are part of the mite superorder Parasitiformes. Adult ticks are approximately 3 to 5 mm in length depending on age, sex, species, and "fullness". Ticks are external parasites, living by ...
s, and vertebrates such as
birds Birds are a group of warm-blooded vertebrates constituting the class Aves (), characterised by feathers, toothless beaked jaws, the laying of hard-shelled eggs, a high metabolic rate, a four-chambered heart, and a strong yet lightweigh ...
,
amphibian Amphibians are tetrapod, four-limbed and ectothermic vertebrates of the Class (biology), class Amphibia. All living amphibians belong to the group Lissamphibia. They inhabit a wide variety of habitats, with most species living within terres ...
s,
reptiles Reptiles, as most commonly defined are the animals in the Class (biology), class Reptilia ( ), a paraphyletic grouping comprising all sauropsid, sauropsids except birds. Living reptiles comprise turtles, crocodilians, Squamata, squamates (lizar ...
,
fish Fish are aquatic, craniate, gill-bearing animals that lack limbs with digits. Included in this definition are the living hagfish, lampreys, and cartilaginous and bony fish as well as various extinct related groups. Approximately 95% of li ...
and
mammals Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur or ...
, including humans. Human infection is often caused by vectors, particularly ticks but also
mosquito Mosquitoes (or mosquitos) are members of a group of almost 3,600 species of small flies within the family Culicidae (from the Latin ''culex'' meaning " gnat"). The word "mosquito" (formed by ''mosca'' and diminutive ''-ito'') is Spanish for "li ...
s,
deer flies Deer flies (also known in some parts of the mid-Atlantic United States as sheep flies) are Hematophagy, bloodsucking insects considered Pest (organism), pests to humans and cattle. They are large flies with large brightly-coloured compound eyes, ...
and horse-flies. Direct contact with infected animals or carcasses is another source. Important reservoir hosts include
lagomorphs The lagomorphs are the members of the taxonomic order Lagomorpha, of which there are two living families: the Leporidae ( hares and rabbits) and the Ochotonidae (pikas). The name of the order is derived from the Ancient Greek ''lagos'' (λα ...
(e.g. rabbits),
rodents Rodents (from Latin , 'to gnaw') are mammals of the order Rodentia (), which are characterized by a single pair of continuously growing incisors in each of the upper and lower jaws. About 40% of all mammal species are rodents. They are nat ...
, galliform birds and
deer Deer or true deer are hoofed ruminant mammals forming the family Cervidae. The two main groups of deer are the Cervinae, including the muntjac, the elk (wapiti), the red deer, and the fallow deer; and the Capreolinae, including the reindeer ...
. Infection via
fomite A fomite () or fomes () is any inanimate object that, when contaminated with or exposed to infectious agents (such as pathogenic bacteria, viruses or fungi), can transfer disease to a new host. Transfer of pathogens by fomites A fomite is any ina ...
s (objects) is also important. Human-to-human transmission has not been demonstrated. ''F. tularensis'' can survive for weeks outside a mammalian host and has been found in water,
grassland A grassland is an area where the vegetation is dominated by grasses (Poaceae). However, sedge (Cyperaceae) and rush (Juncaceae) can also be found along with variable proportions of legumes, like clover, and other herbs. Grasslands occur natur ...
, and
hay Hay is grass, legumes, or other herbaceous plants that have been cut and dried to be stored for use as animal fodder, either for large grazing animals raised as livestock, such as cattle, horses, goats, and sheep, or for smaller domesticat ...
stacks. Aerosols containing the bacteria may be generated by disturbing carcasses due to brush cutting or lawn mowing; as a result, tularemia has been referred to as "lawnmower disease".
Epidemiological Epidemiology is the study and analysis of the distribution (who, when, and where), patterns and determinants of health and disease conditions in a defined population. It is a cornerstone of public health, and shapes policy decisions and evidenc ...
studies have shown a positive correlation between occupations involving the above activities and infection with ''F. tularensis''. Human infection with ''F. tularensis'' can occur by several routes. Portals of entry are through blood and the respiratory system. The most common occurs via skin contact, yielding an ulceroglandular form of the disease. Inhalation of bacteria, particularly biovar ''F. t. tularensis'', leads to the potentially lethal pneumonic tularemia. While the pulmonary and ulceroglandular forms of tularemia are more common, other routes of inoculation have been described and include
oropharyngeal The pharynx (plural: pharynges) is the part of the throat behind the mouth and nasal cavity, and above the oesophagus and trachea (the tubes going down to the stomach and the lungs). It is found in vertebrates and invertebrates, though its struct ...
infection due to consumption of contaminated food or water, and
conjunctival The conjunctiva is a thin mucous membrane that lines the inside of the eyelids and covers the sclera (the white of the eye). It is composed of non-keratinized, stratified squamous epithelium with goblet cells, stratified columnar epithelium a ...
infection due to inoculation at the eye.


Lifecycle

''F. tularensis'' is a facultative intracellular bacterium that is capable of infecting most cell types, but primarily infects
macrophages Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...
in the host organism. Entry into the macrophage occurs by
phagocytosis Phagocytosis () is the process by which a cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm), giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs phagocytosis is ...
and the bacterium is sequestered from the interior of the infected cell by a
phagosome In cell biology, a phagosome is a vesicle formed around a particle engulfed by a phagocyte via phagocytosis. Professional phagocytes include macrophages, neutrophils, and dendritic cells (DCs). A phagosome is formed by the fusion of the cell ...
. ''F. tularensis'' then breaks out of this phagosome into the
cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
and rapidly proliferates. Eventually, the infected cell undergoes
apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes (morphology) and death. These changes incl ...
, and the progeny bacteria are released in a single "burst" event 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 may facilitate degradation of the phagosome. A
hemolysin Hemolysins or haemolysins are lipids and proteins that cause lysis of red blood cells by disrupting the cell membrane. Although the lytic activity of some microbe-derived hemolysins on red blood cells may be of great importance for nutrient acqu ...
activity, named NlyA, with immunological reactivity to ''
Escherichia coli ''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus ''Escher ...
'' anti-HlyA antibody, was identified in biovar ''F. t. novicida''. Acid phosphatase AcpA has been found in other bacteria to act as a hemolysin, whereas in ''Francisella'', its role as a virulence factor is under vigorous debate. ''F. tularensis'' contains type VI secretion system (T6SS), also present in some other pathogenic bacteria. It also contains a number of
ATP-binding cassette The ATP-binding cassette transporters (ABC transporters) are a transport system superfamily that is one of the largest and possibly one of the oldest gene families. It is represented in all extant phyla, from prokaryotes to humans. ABC transpo ...
(ABC) proteins that may be linked to the secretion of virulence factors. ''F. tularensis'' uses
type IV pili A pilus (Latin for 'hair'; plural: ''pili'') is a hair-like appendage found on the surface of many bacteria and archaea. The terms ''pilus'' and '' fimbria'' (Latin for 'fringe'; plural: ''fimbriae'') can be used interchangeably, although some r ...
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'' cells die and are degraded by the macrophage. This protein is located in a putative
pathogenicity island Pathogenicity islands (PAIs), as termed in 1990, are a distinct class of genomic islands acquired by microorganisms through horizontal gene transfer. Pathogenicity islands are found in both animal and plant pathogens. Additionally, PAIs are found i ...
regulated by the transcription factor MglA. ''F. tularensis'', ''
in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...
'', downregulates the immune response of infected cells, a tactic used by a significant number of pathogenic organisms to ensure their replication is (albeit briefly) unhindered by the host
immune system The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinte ...
by blocking the warning signals from the infected cells. This downmodulation of the immune response requires the IglC protein, though again the contributions of IglC and other genes are unclear. 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 asexual replication. Bacteria divide into two daughter cells, each of which contains identical genetic information. Genetic variation may be introduced by
mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
or
horizontal gene transfer Horizontal gene transfer (HGT) or lateral gene transfer (LGT) is the movement of genetic material between Unicellular organism, unicellular and/or multicellular organisms other than by the ("vertical") transmission of DNA from parent to offsprin ...
. The
genome In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding ge ...
of ''F. t. tularensis'' strain SCHU4 has been
sequenced In genetics and biochemistry, sequencing means to determine the primary structure (sometimes incorrectly called the primary sequence) of an unbranched biopolymer. Sequencing results in a symbolic linear depiction known as a sequence which suc ...
. The studies resulting from the sequencing suggest a number of gene-coding regions in the ''F. tularensis'' genome are disrupted by mutations, thus create blocks in a number of metabolic and synthetic pathways required for survival. This indicates ''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
transposon A transposable element (TE, transposon, or jumping gene) is a nucleic acid sequence in DNA that can change its position within a genome, sometimes creating or reversing mutations and altering the cell's genetic identity and genome size. Transpo ...
-like elements resembling counterparts that normally are found in eukaryotic organisms.


Phylogenetics

Much of the known global genetic diversity of ''F. t. holarctica'' is present in
Sweden Sweden, formally the Kingdom of Sweden,The United Nations Group of Experts on Geographical Names states that the country's formal name is the Kingdom of SwedenUNGEGN World Geographical Names, Sweden./ref> is a Nordic country located on ...
.Karlsson E, Svensson K, Lindgren P, Byström M, Sjödin A, Forsman M, Johansson A (2012) The phylogeographic pattern of ''Francisella tularensis'' in Sweden indicates a Scandinavian origin of Eurosiberian tularaemia. Environ Microbiol doi: 10.1111/1462-2920.12052 This suggests this subspecies originated in
Scandinavia Scandinavia; Sámi languages: /. ( ) is a subregion#Europe, subregion in Northern Europe, with strong historical, cultural, and linguistic ties between its constituent peoples. In English usage, ''Scandinavia'' most commonly refers to Denmark, ...
and spread from there to the rest of Eurosiberia.


Use as a biological weapon

When the U.S.
biological warfare Biological warfare, also known as germ warfare, is the use of biological toxins or infectious agents such as bacteria, viruses, insects, and fungi with the intent to kill, harm or incapacitate humans, animals or plants as an act of war. Bio ...
program ended in 1969, ''F. tularensis'' was one of seven standardized biological weapons it had developed as part of German-American cooperation in the 1920s–1930s.Croddy, Eric C. and Hart, C. Perez-Armendariz J., ''Chemical and Biological Warfare'',
Google Books
, Springer, 2002, pp. 30–31, (), accessed October 24, 2008.


Diagnosis, treatment, and prevention

;Diagnosis Infection by ''F. tularensis'' is diagnosed by clinicians based on symptoms and patient history, imaging, and laboratory studies. ;Treatment Tularemia is treated with antibiotics, such as aminoglycosides, tetracyclines, or fluoroquinolones. About 15 proteins were suggested that could facilitate drug and vaccine design pipeline. ;Prevention Preventive measures include preventing bites from ticks, flies, and mosquitos; ensuring that all game is cooked thoroughly; refraining from drinking untreated water and using insect repellents. If working with cultures of ''F. tularensis,'' in the lab, wear a gown, impermeable gloves, mask, and eye protection. When dressing game, wear impermeable gloves. A live attenuated vaccine is available for individuals who are at high risk for exposure such, as laboratory personnel.


Genomics


Francisella Genome Projects
(fro
Genomes OnLine Database

Comparative Analysis of Francisella Genomes
(at DOE's IMG system)


See also

* ''Francisella'' small RNA


References


External links


''Francisella tularensis'' information
from the CDC/National Center for Infectious Diesase:
BioHealthBase Bioinformatics Resource Center
The
National Institute of Allergy and Infectious Disease The National Institute of Allergy and Infectious Diseases (NIAID, ) is one of the 27 institutes and centers that make up the National Institutes of Health (NIH), an agency of the United States Department of Health and Human Services (HHS). NIAID's ...
(NIAID) supports a public database describing the molecular genetics of ''F. tularensis''. The website describes the genes, proteins, and cellular characteristics of the pathogen.
Type strain of ''Francisella tularensis'' at Bac''Dive'' – the Bacterial Diversity Metadatabase
{{Taxonbar, from=Q1003460 Thiotrichales Biological weapons Bacteria described in 1912