Legionella pneumophila, the causative agent of Legionnaires' disease, actively manipulates intracellular processes to establish a replication niche inside their host cells. The establishment of its replication niche requires a functional Icm/Dot type IV secretion system which translocates about 300 effector proteins into the host cells during infection. This enormous number of effectors should be coordinated at the level of gene expression, in order to be expressed and translocated at the correct time and appropriate amounts. One of the predominant ways in bacteria to regulate virulence gene expression is by the use of two-component systems (TCSs). To date, four TCSs have been shown to be involved in the regulation of Icm/Dot effector-encoding genes: The PmrAB and CpxRA TCSs that directly control, and the LetAS and LqsRS TCSs that indirectly control the level of expression of effector-encoding genes. According to our current knowledge, these four TCSs control the expression of about 70 effector-encoding genes. The regulation by different TCSs divides the effectors into groups of co-regulated effector-encoding genes that are probably co-expressed at a similar time during infection and might perform related functions. In addition, examples of interplay between these TCSs were already reported indicating that they form part of a regulatory network that orchestrates the expression of L. pneumophila effector-encoding genes during infection.
