BosR and PlzA reciprocally regulate RpoS function to sustain Borrelia burgdorferi in ticks and mammals

• Published in: The Journal of clinical investigation Vol. 133; no. 5; pp. 1 - 13
• Main Authors: Grassmann, André A, Tokarz, Rafal, Golino, Caroline, McLain, Melissa A, Groshong, Ashley M, Radolf, Justin D, Caimano, Melissa J
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.03.2023
• Subjects: Adaptation; Animals; Arachnids; Arthropods; Bacterial Proteins - genetics; Bacterial Proteins - metabolism; Biomedical research; Borrelia - metabolism; Borrelia burgdorferi; Borrelia burgdorferi - genetics; Causes of; Development and progression; Dialysis; Disease transmission; DNA-directed RNA polymerase; Gene expression; Gene Expression Regulation, Bacterial; Gene regulation; Gene silencing; Genes; Genetic aspects; Genetic transcription; Health aspects; Host-parasite relationships; Infections; Infectious disease; Kinases; Ligands; Lyme disease; Lyme Disease - genetics; Mammals - metabolism; Mice; Microbiology; Oxidative stress; Pathogens; Physiological aspects; Proteins; RNA; RNA polymerase; Sigma Factor - genetics; Sigma Factor - metabolism; Tick-borne diseases; Ticks - genetics; Transcription activation; Transcriptional coactivators; Transcriptomes; Transcriptomics; United States; Infectious disease; Signal transduction; Bacterial infections; Microbiology; Molecular biology
• DOI: 10.1172/JCI166710
• ISSN: 1558-8238; 0021-9738

The RNA polymerase alternative σ factor RpoS in Borrelia burgdorferi (Bb), the Lyme disease pathogen, is responsible for programmatic-positive and -negative gene regulation essential for the spirochete's dual-host enzootic cycle. RpoS is expressed during tick-to-mammal transmission and throughout mammalian infection. Although the mammalian-phase RpoS regulon is well described, its counterpart during the transmission blood meal is unknown. Here, we used Bb-specific transcript enrichment by tick-borne disease capture sequencing (TBDCapSeq) to compare the transcriptomes of WT and ΔrpoS Bb in engorged nymphs and following mammalian host-adaptation within dialysis membrane chambers. TBDCapSeq revealed dramatic changes in the contours of the RpoS regulon within ticks and mammals and further confirmed that RpoS-mediated repression is specific to the mammalian-phase of Bb's enzootic cycle. We also provide evidence that RpoS-dependent gene regulation, including repression of tick-phase genes, is required for persistence in mice. Comparative transcriptomics of engineered Bb strains revealed that the Borrelia oxidative stress response regulator (BosR), a noncanonical Fur family member, and the cyclic diguanosine monophosphate (c-di-GMP) effector PlzA reciprocally regulate the function of RNA polymerase complexed with RpoS. BosR is required for RpoS-mediated transcription activation and repression in addition to its well-defined role promoting transcription of rpoS by the RNA polymerase alternative σ factor RpoN. During transmission, ligand-bound PlzA antagonizes RpoS-mediated repression, presumably acting through BosR.