| Francisella tularensis | |
|---|---|
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| Francisella tularensis bacteria (blue) infecting amacrophage (yellow) | |
Scientific classification | |
| Domain: | Bacteria |
| Kingdom: | Pseudomonadati |
| Phylum: | Pseudomonadota |
| Class: | Gammaproteobacteria |
| Order: | Thiotrichales |
| Family: | Francisellaceae |
| Genus: | Francisella |
| Species: | F. tularensis |
| Binomial name | |
| Francisella tularensis (McCoy and Chapin 1912) Dorofe'ev 1947 | |
Francisella tularensis is apathogenic species ofGram-negativecoccobacillus, anaerobicbacterium.[1] It is nonspore-forming, nonmotile,[2] and the causative agent oftularemia, the pneumonic form of which is often lethal without treatment. It is a fastidious, facultativeintracellular bacterium, which requirescysteine for growth.[3] Due to its low infectious dose, ease of spread by aerosol, and highvirulence,F. tularensis is classified as a Tier 1Select Agent by the U.S. government, along with other potential agents of bioterrorism such asYersinia pestis,Bacillus anthracis, andEbola 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.[4]
This species was discovered in ground squirrels inTulare County, California in 1911.Bacterium tularense was soon isolated byGeorge Walter McCoy (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 thatBacterium tularense was the causative agent oftularemia, after studying several cases with symptoms of the disease. Later, it became known asFrancisella tularensis, in honor of the discovery by Francis.[5][6][7]
The disease was also described in theFukushima region of Japan by Hachiro Ohara in the 1920s, where it was associated with hunting rabbits.[8] 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 asFrancisella dorofeev in former Soviet countries.
Three subspecies (biovars) ofF. tularensis are recognised (as of 2020):[8]
Additionally,F. novicida[9] has sometimes previously been classified asF. t. novicida. It was characterized as a relatively nonvirulentFrancisella; only two tularemia cases in North America have been attributed to the organism, and these were only in severelyimmunocompromised individuals.
Human infection is often caused byvectors, particularly ticks but alsomosquitos,deer flies andhorse-flies. Direct contact with infected animals or carcasses is another source.[8] Important reservoir hosts includelagomorphs (e.g. rabbits),rodents,[8]galliform birds anddeer.[citation needed] Infection viafomites (objects) is also important.[8] Human-to-human transmission has been demonstrated via solid organ transplantation.[10]
F. tularensis can survive for weeks outside a mammalian host[citation needed] and has been found in water,[8]grassland, andhaystacks. 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 studies have shown a positive correlation between occupations involving the above activities and infection withF. tularensis.[citation needed]
Human infection withF. 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,[8] particularly biovarF. t. tularensis,[citation needed] leads to the potentially lethalpneumonic tularemia. While the pulmonary and ulceroglandular forms of tularemia are more common, other routes of inoculation have been described and includeoropharyngeal infection due to consumption of contaminated food or water, andconjunctival infection due to inoculation at the eye.[8]
F. tularensis is a facultative intracellular bacterium that is capable of infecting most cell types, but primarily infectsmacrophages in the host organism.[11] Entry into the macrophage occurs byphagocytosis and the bacterium is sequestered from the interior of the infected cell by aphagosome.[12]F. tularensis then breaks out of this phagosome into thecytosol and rapidly proliferates. Egress from the cytosol requires theFrancisellatype VI secretion system (T6SS).[13] The secreted effector PdpC enables rapid escape into the cytosol (within as little as 30 minutes),[14] while OpiA delays phagolysosomal maturation thus impairing host bacterial killing.[15] Eventually, the infected cell undergoesapoptosis, and the progeny bacteria are released in a single "burst" event[16] to initiate new rounds of infection. Alternatively, uninfected phagocytes can become infected via a process termed merocytophagy, in which an uninfected cell "bites off" part of an infected cell.[17]
The virulence mechanisms forF. 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.[18] Ahemolysin activity, named NlyA, with immunological reactivity toEscherichia coli anti-HlyA antibody, was identified in biovarF. t. novicida.[19] Acid phosphatase AcpA has been found in other bacteria to act as a hemolysin, whereas inFrancisella, its role as a virulence factor is under vigorous debate.
F. tularensis containstype VI secretion system (T6SS), also present in some other pathogenic bacteria.[20]It also contains a number ofATP-binding cassette (ABC) proteins that may be linked to the secretion of virulence factors.[21]F. tularensis usestype IV pili 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 forF. tularensis phagosomal breakout and intracellular replication; in its absence, mutantF. tularensis cells die and are degraded by the macrophage. This protein is located in a putativepathogenicity island regulated by the transcription factor MglA.
F. tularensis,in vitro, 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 hostimmune system 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 inF. tularensis pathogenicity.
Unlike most Gram-negative bacteria with 6fatty acyl tails, thelipopolysaccharide (LPS) ofF. tularensis contains only 4 atypically long acyl chains.[22] This abnormal LPS is poorly recognized by the host, and fails to trigger the robust immune response that most LPS triggers.[23]
Like many other bacteria,F. tularensis undergoesasexual replication. Bacteria divide into twodaughter cells, each of which contains identical genetic information. Genetic variation may be introduced bymutation orhorizontal gene transfer.
Thegenome ofF. t. tularensis strain SCHU4 has beensequenced.[24] The studies resulting from the sequencing suggest a number of gene-coding regions in theF. tularensis genome are disrupted by mutations, thus creating blocks in a number of metabolic and synthetic pathways required for survival. This indicatesF. tularensis has evolved to depend on the host organism for certain nutrients and other processes ordinarily taken care of by these disrupted genes.
TheF. tularensis genome contains unusualtransposon-like elements resembling counterparts that normally are found in eukaryotic organisms.[24]
Much of the known global genetic diversity ofF. t. holarctica is present inSweden.[25] This suggests this subspecies originated inScandinavia and spread from there to the rest of Eurosiberia.
When the U.S.biological warfare 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.[26]
Infection byF. tularensis is diagnosed by clinicians based on symptoms and patient history, imaging, and laboratory studies.
Tularemia is treated with antibiotics, such as aminoglycosides, tetracyclines, or fluoroquinolones. About 15 proteins were suggested that could facilitate drug and vaccine design pipeline.[27]
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 ofF. 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.[28]
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