Essential Role of the Response Regulator Rrp2 in the Infectious Cycle of Borrelia burgdorferi

Abstract

Alteration of surface lipoprotein profiles is a key strategy that the Lyme disease pathogen, Borrelia burgdorferi, has evolved to be maintained within its enzootic cycle between arthropods and mammals. Accumulated evidence indicates that the central regulatory pathway controlling differential gene expression by B. burgdorferi is the RpoN-RpoS pathway (the 54 -S sigma factor cascade). It was previously shown that activation of the RpoN-RpoS pathway is controlled by Rrp2, a two-component response regulator and 54 -dependent transcriptional activator. The role of Rrp2 in the infectious cycle of B. burgdorferi has not been determined heretofore. In this report, we demonstrate that an rrp2 mutant defective in activating 54 -dependent transcription was unable to establish infection in mice, but the rrp2 mutant was capable of surviving within ticks during and after tick feeding. Because the rrp2 mutant was defective in the production of OspC, an outer surface lipoprotein essential for mammalian host infection, we further examined whether the loss of infectivity of the rrp2 mutant was solely due to the inability to produce OspC. While transformation with a shuttle vector carrying ospC under the control of a constitutive flaB promoter restored infection to an ospC mutant in immunodeficient SCID mice, it could not rescue the avirulent phenotype of the rrp2 mutant. These data indicate that, in addition to controlling OspC, Rrp2 controls another factor(s) essential for B. burgdorferi to establish infection in mammals. Furthermore, microarray analyses revealed that 125 and 19 genes were positively and negatively regulated, respectively, by Rrp2, which provides a foundation for future identification of additional Rrp2-dependent virulence determinants in B. burgdorferi.

Live imaging reveals a biphasic mode of dissemination of Borrelia burgdorferi within ticks

“…Abundant evidence has emerged indicating that the Rrp2/RpoN/RpoS pathway serves as a master regulator of the genetic programs required for infection of the mammalian host (19,35,51,(81)(82)(83). The imaging studies presented here provide a structural framework for interpreting the transcriptional events mediated by RpoS during tick-to-mammal transmission.…”

A manganese transporter, BB0219 (BmtA), is required for virulence by the Lyme disease spirochete, Borrelia burgdorferi

“…I. scapularis nymphs or larvae (obtained from the Tick Rearing Facility at Oklahoma State University, Stillwater, OK) were artificially infected with various strains of Bb by using a microinjection technique (11,43) or an immersion method (30) (see SI Methods). After infection, ticks were fed to repletion on separate naïve C3H/HeN mice.…”

“…It is now well established that outer surface (lipo)protein C (OspC), OspA/B, decorin-binding protein B/A (DbpB/A), PncA, and BptA are required by Bb for efficient infection of ticks or mammalian hosts (4)(5)(6)(7)(8)(9)(10). It is also generally accepted that the recently discovered Rrp2-RpoN ( 54 )-RpoS ( S ) regulatory pathway plays prominently in Bb's virulence expression (11)(12)(13)(14).…”

Overexpression of CsrA (BB0184) Alters the Morphology and Antigen Profiles ofBorrelia burgdorferi

“…A central regulatory pathway comprising Rrp2-RpoN-RpoS has been characterized as regulating outer surface protein C (OspC), decorin binding protein A (DbpA), fibronectin binding protein BBK32, and several other borrelial determinants involved in various pathogenic processes (11, 17-20, 41, 88). Mutations in one or more of these regulators have also been characterized as having significant global effects on the transcriptional levels of a large number of ORFs in B. burgdorferi (12,17,20,31,61). Recently, it has also been shown that inactivation of ospAB constitutively activates the Rrp2-RpoNRpoS pathway, indicating mechanisms that are unique to B. burgdorferi and to its survival strategies in the tick vector and mammalian hosts (40).…”