# Control of _Francisella tulareis_ Virulence at Gene Level: Network of Transcription Factors
## 1 Introduction  
_Francisella tulareis_ belongs to the genus Francisella, which is highly diverse comprising a considerable number of species, and the genus is rapidly expanding. Several species exist globally and many species appear adapted to highly specialized environmental niches and are capable of infecting a broad range of mammals and fish. The species _F. tulareis_ encompasses two subspecies pathogenic for humans, _tularensis_ and _holarctica_. _F. novicida_ is usually described as separate species, although it shares >97% nucleotide identity with _F. tulareis_, the former is a rare human pathogen often derived from environmental sources [1]. However, _F. novicida_ is often used as a surrogate for _F. tulareis_, e.g., in genetic studies. _F. tulareis_ is a highly infectious human pathogen causing tulareia [2, 3]. It is an intracellular pathogen, the virulence of which is based on the ability to escape from phagosomes and replicate in the cytosol of the host cell. Subsequently, after rapid intracellular replication, it subverts the immune system [4, 5, 6, 7, 8]. Depending on the route of infection, it may, in severe cases, cause pneumonia [9, 10]. Its virulence is controlled at many levels, including molecular signaling, gene transcription, translation, and many posttranslational modifications. Its pathogenicity depends on the production of bacterial virulence factors, the role of which is to attack the host cell and to suppress the immune response.  
The most important virulence factors of _F. tulareis_ include the capsule [11, 12] and surface lipopolysaccharide ascertaindex layer [13, 14, 15, 16]; membrane vesicles [6, 17, 18]; and secretion systems, especially the Type VI Secretion System (T6 SS) [19, 20, 21, 22]. The latter is composed of proteins encoded by genes from the Francisella pathogenicity island (FPI) (_pdpABCDe_, _iglABCDEFGHI_), _vgrG_, DotU domain-containing protein (_dotU_) [20, 23, 24]. FPI proteins are necessary for Francisella intracellular replication andmutant strains lacking at least one FPI gene are also defective for virulence in vivo [21]. FPI proteins are key components that ensure the ability of _F. tulareis_ to modulate phagosome maturation and to escape into the cytosol of the host cell [21], as exemplified by analysis of the best described FPI protein, intracellular growth locus C (IgIC) [25]. Interestingly, not all FPI proteins are important for intracellular growth, as reported for IgIG [21]; nevertheless, a \(\Delta\)_igIG_ mutant strain exhibited delayed phagosomal escape [26]. FPI gene expression is probably the most important step of Francisella virulence and a detailed understanding of its regulation is essential for the understanding of the _F. tulareis_ pathogenesis.  
Last but not least virulence factors are regulatory proteins that control the transcription of virulence genes, mainly the macrophage growth locus, subunit A (MgIA)/stringent starvation protein A (SspA)/pathogenicity island gene regulator (PigR) complex [27; 28; 29; 30; 31; 32], but also numerous others. Many DNA-binding proteins have been identified in Francisella since its complete genome sequencing [24], but only a few of them are well described and reviewed in Reference [33]. This review will be focused on transcription factors that are important for Francisella pathogenesis (Table 1).