Francisella tularensis

This species was discovered in ground squirrels in Tulare County, California in 1911. Bacterium tularense was soon isolated by George 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 that Bacterium tularense was the causative agent of tularemia, 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 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 (biovars) of F. tularensis are recognised (as of 2020): • F. t. tularensis (or type A), found predominantly in North America, 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 and Asia, but rarely leads to fatal disease. An attenuated live vaccine strain of subspecies F. t. holarctica has been described, though it is not yet fully licensed by the Food and Drug Administration 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; 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 individuals. == Pathogenesis ==

Human infection is often caused by vectors, particularly ticks but also mosquitos, deer flies and horse-flies. Direct contact with infected animals or carcasses is another source. F. tularensis can survive for weeks outside a mammalian host and has been found in water, Entry into the macrophage occurs by phagocytosis and the bacterium is sequestered from the interior of the infected cell by a phagosome. F. tularensis then breaks out of this phagosome into the cytosol and rapidly proliferates. Egress from the cytosol requires the Francisella type VI secretion system (T6SS). The secreted effector PdpC enables rapid escape into the cytosol (within as little as 30 minutes), while OpiA delays phagolysosomal maturation thus impairing host bacterial killing. Eventually, the infected cell undergoes apoptosis, and the progeny bacteria are released in a single "burst" event 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. 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 activity, named NlyA, with immunological reactivity to Escherichia coli 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 (ABC) proteins that may be linked to the secretion of virulence factors. F. tularensis uses type 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 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 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 host immune 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 in F. tularensis pathogenicity. Unlike most Gram-negative bacteria with 6 fatty acyl tails, the lipopolysaccharide (LPS) of F. tularensis contains only 4 atypically long acyl chains. This abnormal LPS is poorly recognized by the host, and fails to trigger the robust immune response that most LPS triggers. == 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 or horizontal gene transfer. The genome of F. t. tularensis strain SCHU4 has been sequenced. The studies resulting from the sequencing suggest a number of gene-coding regions in the F. tularensis genome are disrupted by mutations, thus creating 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-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. This suggests this subspecies originated in Scandinavia and spread from there to the rest of Eurosiberia. ==Use as a biological weapon==

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. ==Diagnosis, treatment, and prevention==

plate showing colonies of F. tularensis 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 (from Genomes OnLine Database) • Comparative Analysis of Francisella Genomes (at DOE's IMG system) ==See also==