A Pair of Highly Conserved Two-Component Systems Participates in the Regulation of the Hypervariable FIR Proteins in DifferentLegionellaSpecies

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Abstract
Legionella pneumophilaand other pathogenicLegionellaspecies multiply inside protozoa and human macrophages by using the Icm/Dot type IV secretion system. The IcmQ protein, which possesses pore-forming activity, and IcmR, which functions as its chaperone, are two essential components of this system. It was previously shown that in 29Legionellaspecies, a large hypervariable-gene family (firgenes) is located upstream from a conservedicmQgene, but although nonhomologous, the FIR proteins were found to function similarly together with their corresponding IcmQ proteins. Alignment of the regulatory regions of 29firgenes revealed that they can be divided into three regulatory groups; the first group contains a binding site for the CpxR response regulator, which was previously shown to regulate theL. pneumophila firgene (icmR); the second group, which includes most of thefirgenes, contains the CpxR binding site and an additional regulatory element that was identified here as a PmrA binding site; and the third group contains only the PmrA binding site. Analysis of the regulatory region of twofirgenes, which included substitutions in the CpxR and PmrA consensus sequences, a controlled expression system, as well as examination of direct binding with mobility shift assays, revealed that both CpxR and PmrA positively regulate the expression of thefirgenes that contain both regulatory elements. The change in the regulation of thefirgenes that occurred during the course of evolution might be required for the adaptation of the differentLegionellaspecies to their specific environmental hosts.