# Cyclic di-GMP Second Messenger Signaling in the Tickborne Relapsing Fever Spirochete, Borrelia turicatae

> **NIH NIH R21** · UNIV OF ARKANSAS FOR MED SCIS · 2022 · $224,272

## Abstract

PROJECT SUMMARY/ABSTRACT
 The vector-borne spirochetes that cause relapsing fever are transmitted to humans by either ticks or human
body lice. Despite identification of the etiological agents of relapsing fever over 100 years ago, very little
information exists regarding their pathogenesis of these bacteria. Relapsing fever is more common in developing
countries, but tickborne relapsing fever (TBRF) also occurs in areas of the U.S. where Ixodes and Ornithodoros
species of ticks, the vectors for TBRF spirochetes, are endemic. During their natural enzootic cycle, vector-borne
spirochetes exist in two distinct niches found within the arthropod vector and the vertebrate. It is well
established that Lyme disease spirochetes must undergo significant changes in global gene expression to allow
them to adapt to these two diverse environments. Cyclic dimeric guanosine monophosphate (c-di-GMP) is an
important second messenger molecule that plays a key role during the enzootic cycle of Borrelia burgdorferi,
but its regulatory contribution in TBRF spirochetes has not been investigated. In this proposal, we will test the
role of the c-di-GMP signaling pathway in promoting adaptation of TBRF spirochetes to the different host
environments encountered during the bacterial natural lifecycle. While we expect c-di-GMP-dependent
signaling to be important for the enzootic cycle of TBRF spirochetes, there are also significant differences
between the pathogenesis and vector biology of Lyme disease Borrelia and TBRF Borrelia that lead us to
anticipate that the relative contribution of c-di-GMP during TBRF spirochete infection and vector colonization
could be unique. To being addressing this, we have inactivated individual components in the c-di-GMP
regulatory system in a low-passage, virulent isolate of B. turicatae. In Specific Aim 1, the phenotypes of these
mutants will be evaluated using the experimental B. turicatae-O. turicata transmission/infection model to define
the importance of the c-di-GMP signaling pathway during the enzootic cycle of B. turicatae. In Specific Aim 2,
we will use these mutants to determine the influence of the c-di-GMP signaling system on B. turicatae global
gene expression and protein production. These aims will provide critical knowledge regarding the regulatory
networks that control B. turicatae adaptation during transmission and infection. Molecular characterization of
the individual c-di-GMP signaling components, their specific roles in virulence regulation, and potential
virulence determinants will be the focus of future R01 grant proposals. Regulators and virulence factors
identified in this project represent potential targets against which future therapeutic interventions and/or
diagnostics for TBRF could be developed.

## Key facts

- **NIH application ID:** 10378138
- **Project number:** 5R21AI156101-02
- **Recipient organization:** UNIV OF ARKANSAS FOR MED SCIS
- **Principal Investigator:** Jon Scott Blevins
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $224,272
- **Award type:** 5
- **Project period:** 2021-03-25 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10378138

## Citation

> US National Institutes of Health, RePORTER application 10378138, Cyclic di-GMP Second Messenger Signaling in the Tickborne Relapsing Fever Spirochete, Borrelia turicatae (5R21AI156101-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10378138. Licensed CC0.

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