F. tularensis is divided into GDC-0941 research buy four BIBW2992 subspecies, where ssp. holarctica (type B) is most widely spread and found in the major part of Europe, Asia, and North

America. F. tularensis ssp. tularensis (type A) is found exclusively in North America and ssp. mediasiatica in Central Asia. Finally, ssp. novicida has been isolated in several locations in North America, as well as in Australia [3, 4]. Human infections are mainly caused by type A or type B strains, where type A strains are significantly more virulent than type B strains. Our knowledge regarding virulence determinants in F. tularensis is rather limited. However, available genome information [5, 6] together with development of genetic tools [7], has resulted in increased understanding of the molecular mechanisms of F. tularensis infections. The genome of F. tularensis encodes gene clusters involved in secretion and assembly of type IV pili (Tfp) [5]. Tfp are complex adhesins involved in important host cell interactions for human pathogens like Neisseria spp., Pseudomonas aeruginosa and Vibrio cholerae [8–11]. The pilus fiber is composed of one major pilin subunit and several additional minor pilins required for function and/or assembly of LXH254 the pilus [12, 13]. However, the exact roles of the minor pilins are still not completely understood. The

pilus is translocated to the cell surface via the secretin, PilQ, which forms a pore in the outer membrane through which the pilus is transported and extended [14]. PilD is a peptidase cleaving the prepilin subunits [11] and PilC is a transmembrane protein spanning across the plasma membrane [15]. Furthermore,

two ATPases, PilB and PilT, are involved in extension and retraction, of the pilus [16, 17]. In some bacteria Tfp can mediate twitching motility, an activity that is PilT dependent [18]. There is evidence that F. tularensis expresses Tfp-like surface structures on the bacterial surface [19–21], and the putative pilin, PilA, has been shown to be required for virulence of type B strains in a mouse infection model [22]. Interestingly, due to direct repeat mediated deletion, the pilA Methamphetamine gene has been lost in the attenuated live vaccine strain LVS [22, 23], supporting the significance of PilA for virulence [24]. There are also other potentially significant differences between different F. tularensis subspecies. In ssp. novicida that is non-pathogenic for humans, PilA differs in the amino acid sequence compared to the virulent type A strain SCHU S4 [25]. On the contrary, pilA of virulent type B strains is essentially identical to the corresponding gene in type A strains, however, several other differences are apparent between the two subspecies. Two predicted pilin genes, pilE and pilV, and the ATPase encoding gene, pilT, are pseudogenes in type B strains [19, 21, 22, 26].