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

Award Number: R21AI156101
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Allergy and Infectious Diseases Research	000	2	4/8/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $224,272 )
2022	2022	UNIVERSITY OF ARKANSAS SYSTEM	4301 W MARKHAM ST SLOT 812 BIO-MED BLDG 1 STE 102	LITTLE ROCK	AR	72205	PULASKI	USA	Allergy and Infectious Diseases Research	000	2	2/10/2022	NON-COMPETING CONTINUATION	$224,272
														Subtotal = $224,272

Issue Date FY: 2021 ( Subtotal = $199,611 )
2021	2021	UNIVERSITY OF ARKANSAS SYSTEM	4301 W MARKHAM ST SLOT 812 BIO-MED BLDG 1 STE 102	LITTLE ROCK	AR	72205	PULASKI	USA	Allergy and Infectious Diseases Research	000	1	3/25/2021	NEW	$199,611
														Subtotal = $199,611

Grand Total All Awards = $423,883

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

Award Number: R21AI156101

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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