The oligopeptide ABC transporter OppA4 negatively regulates the virulence factor OspC production of the Lyme disease pathogen

Abstract

Borrelia burgdorferi sensu lato, the agent of Lyme disease, exists in nature through a complex enzootic life cycle that involves both ticks and mammals. The B. burgdorferi genome encodes five Oligopeptide ABC transporters (Opp) that are predicted to be involve in transport of various nutrients. Previously, it was reported that OppA5 is important for the optimal production of OspC, a major virulence factor of B. burgdorferi. In this study, possible role of another Oligopeptide ABC transporter, OppA4 in ospC expression was investigated by construction of an oppA4 deletion mutant and the complemented strain. Inactivation of oppA4 resulted an increased production of OspC, suggesting that OppA4 has a negative impact on ospC expression. Expression of ospC is controlled by Rrp2-RpoN-RpoS, the central pathway essential for mammal infection. We showed that increased ospC expression in the oppA4 mutant was due to an increased rpoS expression. We then further investigated how OppA4 negatively regulates this pathway. Two regulators, BosR and BadR, are known to positively and negatively, respectively, regulate the Rrp2-RpoN-RpoS pathway. We found that deletion of oppA4 resulted in an increased level of BosR. Previous reports showed that bosR is mainly regulated at the post-transcriptional level by other factors. However, OppA4 appears to negatively regulate bosR expression at the transcriptional level. The finding of OppA4 involved in regulation of the Rrp2-RpoN-RpoS pathway further reinforces the importance of nutritional virulence to the enzootic cycle of B. burgdorferi.

Host-specific functional compartmentalization within the oligopeptide transporter during the Borrelia burgdorferi enzootic cycle

“…Zhou et al . [ 42 ] recently noted that expression of OspC is dysregulated in an oppA4 mutant; therefore, we confirmed that our mutants temperature-shifts normally ( S1C Fig ). For complementation, we inserted the oppA1 or oppA2 coding regions into cp26, each preceded by the 500 bp upstream of oppA1 , which contains the native operonic promoter ( Fig 1A ) [ 17 ].…”

DksA-dependent regulation of RpoS contributes to Borrelia burgdorferi tick-borne transmission and mammalian infectivity

“…However, both Rel bbu and DksA contribute to the expression of ABC-type oligopeptide transporter genes [ 11 , 25 ]. Oligopeptide transporters have also been linked to expression of virulence genes like OspC [ 81 , 82 ]. However, the interplay between the pH environment, ATP levels, oligopeptide transporters, DksA and (p)ppGpp requires further investigation.…”

Borrelia burgdorferi spatiotemporal regulation of transcriptional regulator bosR and decorin binding protein during murine infection

“…Expression of bosR is also induced during nutrient stress in a Rel Bbu , responsible for the synthesis and hydrolysis of (p)ppGpp, dependent manner 65 . BadR, OppA4, and CsrA have proposed roles in bosR transcriptional regulation 64 , 66 – 68 . BadR and OppA4 repress bosR expression and the presence of CsrA is responsible for an increase in bosR transcription.…”