Figure 4. Regulation of gene expression in Borrelia burgdorferi.

a | The histidine kinase 1 (Hk1)–response regulatory protein 1 (Rrp1) and alternative RNA polymerase σ-factor RpoS global regulatory systems. Binding of unidentified ligands to the periplasmic sensor domains (D1 and D2) of the hybrid histidine kinase Hk1 initiates a phosphorelay that activates the diguanylyl cyclase activity of Rrp1, resulting in the production of cyclic di-GMP (c-di-GMP)^55–57,128. Phosphodiesterase A (PdeA) and PdeB degrade c-di-GMP to 5′-phosphoguanylyl-(3′– 5′)-guanosine (pGpG) and GMP, respectively^58,59. Activation of Rrp2 in vitro and in vivo occurs via the high-energy phosphoryl donor acetyl-phosphate rather than by its presumptive cognate histidine kinase, Hk2 (REF. 48). The function of Hk2 is currently unknown. Phosphorylated Rrp2, Borrelia oxidative stress regulator (BosR) and RpoN initiate transcription of rpoS^{37,38,42–47}. This is depicted as a trimeric complex, but the precise interactions between these proteins have yet to be determined. Putative BosR-binding sites (BSs) containing the direct repeat sequence TAAATTAAAT are shown⁴⁷; −24/−12 is the RpoN-binding site in the rpoS promoter⁴⁷. RpoS in turn induces the expression of genes that are required during the mammalian-host phase of the spirochaete life cycle and represses the expression of tick-phase genes.b | Expression of the Hk1–Rrp1 and RpoS global regulatory systems during the B. burgdorferi life cycle^{37,38,55–57,67,79}. In the flat nymph, both the Hk1–Rrp1 and the Rrp2–RpoN–RpoS systems are inactive and only tick-phase genes are expressed. The nymphal blood meal activates both the Hk1 Rrp1 and Rrp2–RpoN–RpoS pathways. Expression of mammalian-phase genes begins in concert with downregulation of tick-phase genes. Following inoculation into a mammalian host, the spirochaetes complete the process of adaptation; the Hk1–Rrp1 pathway is inactive, the Rrp2–RpoN–RpoS pathway is active, mammalian-phase genes are expressed and tick-phase genes are repressed. During larval acquisition of spirochaetes, Hk1–Rrp1 is activated, probably at the feeding site, whereas the Rrp2–RpoN–RpoS system is inactivated. Mammalian-phase genes are repressed, expression of tick-phase genes begins and ingested spirochaetes bind to the larval midgut epithelium via OspA and possibly other receptors^64–66. GGDEF, a conserved motif present in diguanylyl cyclases¹²⁸; Hpt, histidine-containing phosphotransfer domain⁵⁵; HTH, helix–turn–helix doain; N, amino; PAS, putative sensor domain for Hk2; Rec, receiver domain.