YebC regulates variable surface antigen VlsE expression and is required for host immune evasion in Borrelia burgdorferi.

Borrelia burgdorferi, the Lyme disease pathogen causes persistent infection by evading the host immune response. Differential expression of the surface-exposed lipoprotein VlsE that undergoes antigenic variation is a key immune evasion strategy employed byB.burgdorferi. Most studies focused on the mechanism of VlsE antigen variation, but little is known about VlsE regulation and factor(s) that regulates differentialvlsEexpression. In this study, we investigated BB0025, a putative YebC family transcriptional regulator (and hence designated BB0025 as YebC ofB.burgdorferiherein). We constructedyebCmutant and complemented strain in an infectious strain ofB.burgdorferi. TheyebCmutant could infect immunocompromised SCID mice but not immunocompetent mice, suggesting that YebC plays an important role in evading host adaptive immunity. RNA-seq analyses identifiedvlsEas one of the genes whose expression was most affected by YebC. Quantitative RT-PCR and Western blot analyses confirmed thatvlsEexpression was dependent on YebC.In vitro, YebC and VlsE were co-regulated in response to growth temperature. In mice, bothyebCandvlsEwere inversely expressed withospCin response to the host adaptive immune response. Furthermore, EMSA proved that YebC directly binds to thevlsEpromoter, suggesting a direct transcriptional control. These data demonstrate that YebC is a new regulator that modulates expression ofvlsEand other genes important for spirochetal infection and immune evasion in the mammalian host. Author summary The Lyme disease pathogen evolves strategies to subvert host immune responses to cause persistent infection. Antigen variation is a common strategy employed by some pathogens to escape immune recognition and clearance. The VlsE antigen variation system, discovered in 1997, is one such mechanism by whichBorrelia burgdorferi, evades host immune responses.vlsEexpression increases concomitantly with downregulation of the major immunodominant surface lipoprotein OspC in response to host adaptive immune response activation. But factors that regulates the differential expression ofvlsEhave not been well studied. In present study, we identified a key transcription factor, YebC (BB0025), that regulatesvlsEexpression. A mutant lacking YebC has decreased levels of VlsE and was attenuated in immunocompetent mice but was virulent in immunocompromised mice. Identification of YebC as a regulator forvlsEsets the foundation to further study how the pathogen senses the immune pressure to activate the VlsE antigenic variation system and provides a potential therapeutic target to combat persistent Lyme disease.