# Control of _Francisella tulareis_ Virulence at Gene Level: Network of Transcription Factors
## 2 Transcription Factors Involved in Regulation of the FPI  
### MgIA/SspA Complex Directly Regulates FPI  
One of the best described transcriptional regulators of _F. tulareis_ is the MgIA protein (macrophage growth locus, subunit A). The protein was identified as necessary for _F. novicida_ replication in host cells [34; 35] and a mutant strain lacking the _mgIA_ gene is attenuated in a mouse model of infection. Notably, the mutant does not elicit a protective immune response against infection with the fully virulent parental _F. tulareis_ strain [27; 28]. MgIA is a transcription factor, which regulates up to 100 genes, including the FPI genes [27; 28; 29]. The most important genes that are associated with _F. tulareis_ or _F. novicida_ virulence and are known to be positively regulated by MgIA are listed in Table 2.  
\begin{table}
\begin{tabular}{c c c c c c} \hline \hline  & **Locus Tag** & & **Gene** & **Main Function** & **Reference** \\ \hline
**Schu S4** & **LVS** & **UII2** & & & \\ \hline FIT\_1275 & FIT\_1185 & FIT\_1290 & _mgIA_ & \ \begin{tabular}{c} interacting with SpAp, regulation of FPI genes, necessary for intracellular replication \\ \end{tabular}  & [27; 28; 29; 30; 34; 35] \\ \hline FIT\_0458 & FIT\_1606 & FIT\_0549 & _sppA_ & \begin{tabular}{c} interacting with MgIA, regulation of FPI genes, necessary for stress response \\ \end{tabular}  & [28; 30; 34; 36] \\ \hline FIT\_0383 & FIT\_0449 & FIT\_0480 & _pigR_ & interacting with MgIA/SspA, regulation of FPI genes & [31; 32; 37; 38; 39; 40; 41] \\ \hline FIT\_0627 & FIT\_0895 & FIT\_1054 & _hppA_ & global regulator, DNA non-specific binding protein & [42] \\ \hline FIT\_0630 & FIT\_0898 & FIT\_1051 & _hfp_ & RNA-binding protein, necessary for stress response, negative regulator of _php_ operon & [43; 44; 45] \\ \hline FIT\_0748 & FIT\_1364 & FIT\_0720 & _icIR_ & important only for _F. necivida_ virulence in vivo & [46; 47; 48] \\ \hline FIT\_0556c & FIT\_1014 & FIT\_0959 & _avgR_ & regulation of genes involved in oxidative stress response & [49; 50] \\ \hline FIT\_1255c & FIT\_0689 & FIT\_1274 & _amcC_ & global regulator, active during oxidative stress conditions, regulation of some FPI genes and tricarboxylic acid (TCA) & [51] \\ \hline FIT\_0305 & FIT\_1831 & FIT\_1681 & _far_ & regulation of iron concentration & [52; 53; 54; 55] \\ \hline FIT\_0350 & FIT\_0261 & FIT\_0264 & _rppA1_ & RNAP subunit A1, gene transcription & [30; 56] \\ \hline FIT\_1442c & FIT\_0616 & FIT\_1412 & _rppA2_ & RNAP subunit A2, gene transcription & [30; 56] \\ \hline FIT\_0144 & FIT\_1744 & FIT\_1758 & _rppA_ & RNAP subunit B2, gene transcription & [30] \\ \hline FIT\_0145 & FIT\_1743 & FIT\_1567 & _rppA_ & RNAP subunit B, gene transcription & [30] \\ \hline FIT\_0703 & FIT\_1533 & FIT\_0613 & _rppA_ & RNAP subunit B, gene transcription & [30] \\ \hline FIT\_1035c & FIT\_1050 & FIT\_0913 & _rppA_ & sigma factor 70, major sigma factor & [30; 57] \\ \hline FIT\_1112c & FIT\_0851 & FIT\_1092 & _rpctl_ & sigma factor 32, regulation of heat shock proteins & [58; 59; 60; 61; 62; 63; 64; 65; 66; 67; 68; 69; 70; 71; 72; 73; 74; 75; 76; 77; 78; 79; 80; 81; 82; 83; 84; 85; 86; 87; 88; 89; 90; 91; 92; 93; 94; 95; 96; 97; 98; 99; 99; 99; 97; 98; 99; 99; 100; 99; 101; 102; 103; 104; 105; 106; 107; 108; 109; 113; 114; 115; 116; 117; 118; 119; 120; 121; 122; 123; 124; 125; 126; 127; 128; 129; 130; 131; 132; 133; 134; 135; 136; 137; 138; 139; 140; 141; 142; 143; 144; 145; 146; 147; 148; 149; 150; 151; 152; 153; 1 The MgIA protein directly interacts with the SspA protein (Stringent starvation protein A), and this interaction is unique for Francisella genus. The heterodimer MgIA/SspA further binds to RNA polymerase (RNAP). In other bacteria, SspA interacts with RNAP as a homodimer [39]. The activity of SspA was especially notable during starvation conditions and its transcription activity is connected with genes that are important and necessary during various stress conditions [28; 34].