Deciphering borrelia burgdorferi rpos regulatory networks in ticks and mammals
Active Project Grant Awarded Last action
- Award ID
- R01AI192838
- Recipient
-
University Of Connecticut Health Center UEI H6D6JMXJXDE6
- Awarding agency
-
National Institute of Allergy and Infectious Diseases
National Institutes of Health, Department of Health and Human Services
- Obligated
- $2,025,029
Award facts
- Assistance listing
- 93.855 Allergy and Infectious Diseases Research
- Completion date 24% complete
- Place of performance
- Farmington, CT 06030, USA
Award details come from USAspending.gov.
Description
- Abstract
- Borrelia burgdorferi (BB) is maintained in nature within an enzootic cycle involving a mammalian reservoir host and a tick vector. To sustain this dual-host lifestyle, BB must remodel its transcriptome as IT shuttles between these two host milieus. The rpon/rpos pathway is central to borrelial gene regulation. In addition to upregulating genes required for tick transmission and mammalian infection, this pathway represses tick-phase genes, hence its designation as the `gatekeeper'. Activation of the spirochete's other major pathway, HK1/RRP1, results in synthesis of the second messenger C-DI-GMP, which is required for survival in ticks. C-DI-GMP exerts its regulatory effect via the effector protein plza. Using a novel transcriptomic approach, tbdcapseq, we compared the rpos regulons during the nymphal blood meal and mammalian host-adaptation. These analyses established unequivocally that the contours of the rpos regulon differ dramatically during the tick and mammalian phases and that rpos-mediated repression occurs exclusively within mammals. Unexpectedly, we found that deletion of bosr in an iptg-inducible rpos strain diminished expression of rpos-upregulated genes and abrogated rpos-mediated repression. Thus, in addition to its well-recognized function as a cofactor for rpon-dependent transcription of rpos, bosr also plays an essential downstream role modulating promoter recognition by rnap-rpos. Using a BB strain that synthesizes C-DI-GMP constitutively, we made the intriguing observation that liganded-plza (PLZALIG) exerts a `brake' effect on rnap-rpos, antagonizing rpos-mediated repression and diminishing transcription of rpos-upregulated genes. Remarkably, the effect of PLZALIG on rnap- rpos mirrors bosr-deficiency. These findings lead to our central hypothesis that PLZALIG and bosr determine the contours of the rpos regulon by exerting reciprocal effects on rnap-rpos. In aim 1, we will determine how DNA binding by bosr shapes the rpos regulon and investigate the mechanism underlying rpos-mediated repression. Experiments in aim 2 will investigate two possible mechanisms to explain the PLZALIG brake. Lastly, in aim 3, we will assess the contributions of other regulatory factors to modulation of the tick- and mammalian-phase rpos regulons. Our long-term objective is to develop a holistic understanding of how the rpon/rpos regulatory networks orchestrate gene expression to sustain BB in nature.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $744,771 | |
| Amendment | $0 | |
| Amendment | $0 | |
| Amendment | $640,129 | |
| Original award | $640,129 |
Subawards
| Subrecipient | Amount | Awarded |
|---|---|---|
| Creighton University | $120,000 |
Quick answers
Who received award R01AI192838?
R01AI192838 was awarded to University Of Connecticut Health Center by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on September 1, 2025.
How much is award R01AI192838 worth?
$2,025,029 has been obligated on R01AI192838.
On GovTribe
See this award's full record
- Every transaction and subaward
- The recipient's other awards and teaming partners
- Similar grant awards
- Ask GovTribe AI about this award