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Anaplasma Phagocytophilum Modulate Tick Gene Expression for its Survival and Transmission from the Vector Host

Award Number: R01AI130116
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 In the United States, Ixodes scapularis ticks harbor and transmit several pathogens including human anaplasmosis bacterial agent Anaplasma phagocytophilum. This bacterium is transmitted to the vertebrate host by an infected tick bite. Several studies have addressed molecular mechanisms that A. phagocytophilum uses to survive in the mammalian host. Relatively, few studies have clearly defined the molecular strategies that this bacterium uses to survive in ticks. In the previous funding period, we performed a comprehensive molecular analysis on I. scapularis organic anion transporting polypeptides 4056 (IsOATP4056) and genes involved in the tryptophan metabolism pathway in A. phagocytophilum-tick interactions. We made substantial progress and have published several research articles showing importance of IsOATP4056 and the tryptophan pathway in the survival and transmission of A. phagocytophilum from ticks to the naïve vertebrate host. Passive Immunization with IsOATP4056 antibodies impaired A. phagocytophilum transmission from ticks to the vertebrate host. Anaplasma phagocytophilum upregulates IsOATP4056 and activates the tryptophan pathway leading to the increased synthesis of endogenous levels of tryptophan metabolite, Xanthurenic acid (XA). The increased XA prevents the build-up of reactive oxygen species facilitating bacterial survival in tick cells. In addition, A. phagocytophilum activates the XA-mediated p38-MAPK pathway to inhibit tick cell death thereby facilitating the survival of both the bacterial agent and its vector host. We also reported a novel role for XA in the transcriptional activation of isoatp4056 gene expression. Furthermore, A. phagocytophilum downregulates microRNA (miR133) that targets isoatp4056 for its survival and transmission from vector to the vertebrate host. These findings from our previous funding period provide a strong rationale for the proposed aims for this R01 (competing renewal) application. In Aim 1, we propose to understand the mechanism of how passive immunization affects the transmission of A. phagocytophilum from ticks to the vertebrate host. In Aim 2, we will analyze whether targeting IsOATP4056 via active immunization or OATP inhibitor treatment affects the transmission of A. phagocytophilum from ticks to the vertebrate host. In Aim 3, we will characterize XA-mediated regulation of miRNAs that are important in regulating gene expression during A. phagocytophilum survival and transmission from infected ticks to the naïve host. Based on the success in the previous funding period and the aims proposed in this renewal application, we believe that this could be a transformative study that not only serves as a model to study intimate relationships established by pathogens with their arthropod vectors but may also lead in the development of new strategies to interrupt the transmission of this and perhaps other rickettsial bacteria of medical importance.


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 = $357,388 )
2024	2024	UNIVERSITY OF TENNESSEE	201 ANDY HOLT TOWER	KNOXVILLE	TN	37996	KNOX	USA	Allergy and Infectious Diseases Research	000	7	7/9/2024	COMPETING CONTINUATION	$357,388
														Subtotal = $357,388

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	UNIVERSITY OF TENNESSEE	201 ANDY HOLT TOWER	KNOXVILLE	TN	37996	KNOX	USA	Allergy and Infectious Diseases Research	000	6	5/31/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = -$214 )
2022	2019	OLD DOMINION UNIVERSITY	5115 HAMPTON BLVD	NORFOLK	VA	23529	NORFOLK CITY	USA	Allergy and Infectious Diseases Research	002	3	6/29/2022	NON-COMPETING CONTINUATION	-$214
2022	2018	OLD DOMINION UNIVERSITY	5115 HAMPTON BLVD	NORFOLK	VA	23529	NORFOLK CITY	USA	Allergy and Infectious Diseases Research	001	2	6/29/2022	NON-COMPETING CONTINUATION	$0
2022	2017	OLD DOMINION UNIVERSITY	5115 HAMPTON BLVD	NORFOLK	VA	23529	NORFOLK CITY	USA	Allergy and Infectious Diseases Research	000	1	6/29/2022	NEW	$0
														Subtotal = -$214

Issue Date FY: 2021 ( Subtotal = $337,500 )
2021	2021	UNIVERSITY OF TENNESSEE	1331 CIR PARK DR	KNOXVILLE	TN	37916	KNOX	USA	Allergy and Infectious Diseases Research	002	6	6/3/2021	NON-COMPETING CONTINUATION	$362,500
2021	2020	UNIVERSITY OF TENNESSEE	1331 CIR PARK DR	KNOXVILLE	TN	37916	KNOX	USA	Allergy and Infectious Diseases Research	004	5	9/2/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$223,477
2021	2020	OLD DOMINION UNIVERSITY	5115 HAMPTON BLVD	NORFOLK	VA	23529	NORFOLK CITY	USA	Allergy and Infectious Diseases Research	000	4	3/18/2021	NON-COMPETING CONTINUATION	-$387,500
2021	2020	UNIVERSITY OF TENNESSEE	1331 CIR PARK DR	KNOXVILLE	TN	37916	KNOX	USA	Allergy and Infectious Diseases Research	001	5	3/18/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$362,500
2021	2019	OLD DOMINION UNIVERSITY	5115 HAMPTON BLVD	NORFOLK	VA	23529	NORFOLK CITY	USA	Allergy and Infectious Diseases Research	003	3	9/2/2021	NON-COMPETING CONTINUATION	-$223,477
														Subtotal = $337,500

Issue Date FY: 2020 ( Subtotal = $387,500 )
2020	2020	OLD DOMINION UNIVERSITY	5115 HAMPTON BLVD	NORFOLK	VA	23529	NORFOLK CITY	USA	Allergy and Infectious Diseases Research	000	4	6/26/2020	NON-COMPETING CONTINUATION	$387,500
														Subtotal = $387,500

Issue Date FY: 2019 ( Subtotal = $387,500 )
2019	2019	OLD DOMINION UNIVERSITY	5115 HAMPTON BLVD	NORFOLK	VA	23529	NORFOLK CITY	USA	Allergy and Infectious Diseases Research	000	3	6/17/2019	NON-COMPETING CONTINUATION	$387,500
														Subtotal = $387,500

Issue Date FY: 2018 ( Subtotal = $387,500 )
2018	2018	OLD DOMINION UNIVERSITY	5115 HAMPTON BLVD	NORFOLK	VA	23529	NORFOLK CITY	USA	Allergy and Infectious Diseases Research	000	2	5/24/2018	NON-COMPETING CONTINUATION	$387,500
														Subtotal = $387,500

Issue Date FY: 2017 ( Subtotal = $387,500 )
2017	2017	OLD DOMINION UNIVERSITY	5115 HAMPTON BLVD	NORFOLK	VA	23529	NORFOLK CITY	USA	Allergy and Infectious Diseases Research	000	1	7/18/2017	NEW	$387,500
														Subtotal = $387,500

Grand Total All Awards = $2,244,674

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Anaplasma Phagocytophilum Modulate Tick Gene Expression for its Survival and Transmission from the Vector Host

Award Number: R01AI130116

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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