Abstract
Bacteria alter gene expression in response to changes in their environment through various mechanisms that include signal transduction systems. These signal transduction systems use membrane histidine kinase with sensing domains to mediate phosphotransfer to DNA-binding proteins that alter the level of gene expression. Such regulators are called two-component systems (TCSs). TCSs integrate external signals and information from stress pathways, central metabolism and other global regulators, thus playing an important role as part of the overall regulatory network. This review will focus on the knowledge of TCSs in the Gram-negative bacterium, Francisella tularensis, a biothreat agent with a wide range of potential hosts and a significant ability to cause disease. While TCSs have been well-studied in several bacterial pathogens, they have not been well-studied in non-model organisms, such as F. tularensis and its subspecies, whose canonical TCS content surprisingly ranges from few to none. Additionally, of those TCS genes present, many are orphan components, including KdpDE, QseC, QseB/PmrA, and an unnamed two-component system (FTN_1452/FTN_1453). We discuss recent advances in this field related to the role of TCSs in Francisella physiology and pathogenesis and compare the TCS genes present in human virulent versus. environmental species and subspecies of Francisella.
Highlights
While there have been 30 or more paired two-component systems identified in E. coli and other well-studied model organisms and pathogens (Yoshida et al, 2015), very few TCS genes have been identified in the non-model organism Francisella
The use of an inhibitor of QseC, LED209, was able to significantly protect mice from a lethal infection by F. tularensis SchuS4 (Rasko et al, 2008), and LED209 significantly reduced the expression of several genes in the Francisella Pathogenicity Island (FPI), including iglC. These results suggest that LED209-reduced FPI expression may be associated with the reduced virulence (Rasko et al, 2008)
All Francisella genomes examined to date contain QseB/PmrA and QseC (Figure 4; Supplemental Table 1), suggesting that these two highly conserved genes play essential roles in the life-cycle of this organism
Summary
Bacteria alter their gene expression in response to changes in their environment through various mechanisms, including signal transduction systems. Signal inputs or ligands, such as fatty-acids (e.g., diffusible signal factors [DSF]) or other small molecules are detected within the periplasmic space by the SK sensing domain This signal is transmitted across the membrane to activate the intracellular Histidine kinase domain (Figure 1). Signal transduction from the membrane-associated histidine kinase PA1396 to the DNA-binding regulator PA1397 involves a separate histidine transfer domain protein (Ryan et al, 2015) In model organisms, such as Escherichia (E.) coli, TCS are well-studied and there are a large number of TCS proteins; as many as 30 histidine kinases and 32 RRs have been identified (Pruss, 2017). This review serves to summarize the literature on the TCSs present in Francisella, and to explore what is known about their role in Francisella physiology and pathogenesis
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