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Regulation of the physiology and function of the digestive vacuole in Toxoplasma gondii

Award Number: R01AI143707
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/10/2019
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Regulation of the physiology and function of the digestive vacuole in Toxoplasma gondii - PROJECT SUMMARY/ABSTRACT Toxoplasma gondii with the ability to use foodborne, zoonotic, and congenital routes of transmission is an apicomplexan parasite that can cause severe infectious disease in the immunocompromised human population. A few antibiotics are commercially available to treat Toxoplasma infections. However, their strong side effects and teratogenicity limit their use in certain human populations. Inhibition of fundamental nutrient metabolism specific to this parasite will define new drug targets and assist the development of novel drugs to manage T. gondii infection. Our previous studies revealed that Toxoplasma encodes an ortholog of Plasmodium chloroquine resistance transporter (TgCRT), and localized it in the digestive vacuole, termed the Vacuolar Compartment/Plant-Like Vacuole (VAC/PLV, VAC hereafter). Our preliminary data found that the TgCRT-deficient parasites swelled their VACs ~15-fold. These results led to our central hypotheses: (1) the TgCRT serves as a polyspecific transporter to regulate the VAC physiology and function in Toxoplasma, and (2) the TgCRT cooperates with a multidrug resistance transporter-like protein in the VAC to mediate nutrient export, thereby adjusting the microenvironment within the VAC. Towards these hypotheses, we have revealed that the swollen VAC disrupts the parasite’s endolysosomal system and decreases transcript and protein abundances of VAC-associated proteases. We discovered that inhibition of proteolysis within the VAC shrinks its swollen phenotype in TgCRT-null mutant. We have also identified that a Toxoplasma ortholog of Plasmodium multidrug resistance transporter (TgMDR) is localized in the VAC and significantly increased at the level of transcription in the parasites when TgCRT is absent. Last, we determined that TgCRT transports chloroquine by heterologous expression of TgCRT in yeast, suggesting that TgCRT is indeed a functional transporter and providing an amenable system to understand the native functions of TgCRT and other VAC-localizing transporters. Guided by our compelling preliminary studies, we propose three specific aims to characterize the native functions of TgCRT and TgMDR, and how they functionally interact together to regulate VAC physiology and function by serving as nutrient transporters: (1) Quantify the physiological environment within the VAC; (2) Measure the transport of small nutrient solutes by CRT; and (3) Determine the functional relationship between TgCRT and TgMDR in the regulation of the VAC morphology and physiology. Our proposed research will broadly impact the field by characterizing the molecular mechanisms by which Toxoplasma parasites regulate the physiology and function of their digestive vacuoles. Our studies will also help comprehend the native functions of TgCRT and TgMDR, and such knowledge can be generalized to expand understanding of their orthologs in other apicomplexan parasites and organisms.


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: 2026 ( Subtotal = -$1,071 )
2026	2024	CLEMSON UNIVERSITY	201 SIKES HALL	CLEMSON	SC	29634	PICKENS	USA	Allergy and Infectious Diseases Research	000	5	4/20/2026	NON-COMPETING CONTINUATION	-$1,071
														Subtotal = -$1,071

Issue Date FY: 2024 ( Subtotal = $365,542 )
2024	2024	CLEMSON UNIVERSITY	201 SIKES HALL	CLEMSON	SC	29634	PICKENS	USA	Allergy and Infectious Diseases Research	000	5	11/8/2023	NON-COMPETING CONTINUATION	$328,987
2024	2024	CLEMSON UNIVERSITY	201 SIKES HALL	CLEMSON	SC	29634	PICKENS	USA	Allergy and Infectious Diseases Research	001	5	5/16/2024	NON-COMPETING CONTINUATION	$36,555
														Subtotal = $365,542

Issue Date FY: 2023 ( Subtotal = $366,194 )
2023	2023	CLEMSON UNIVERSITY	201 SIKES HALL	CLEMSON	SC	29634	PICKENS	USA	Allergy and Infectious Diseases Research	000	4	11/17/2022	NON-COMPETING CONTINUATION	$366,194
														Subtotal = $366,194

Issue Date FY: 2022 ( Subtotal = $366,814 )
2022	2022	CLEMSON UNIVERSITY	201 SIKES HALL	CLEMSON	SC	29634	PICKENS	USA	Allergy and Infectious Diseases Research	000	3	11/19/2021	NON-COMPETING CONTINUATION	$366,814
														Subtotal = $366,814

Issue Date FY: 2021 ( Subtotal = $367,404 )
2021	2021	CLEMSON UNIVERSITY	201 SIKES HALL	CLEMSON	SC	29634	PICKENS	USA	Allergy and Infectious Diseases Research	000	2	11/18/2020	NON-COMPETING CONTINUATION	$367,404
														Subtotal = $367,404

Issue Date FY: 2020 ( Subtotal = $381,090 )
2020	2020	CLEMSON UNIVERSITY	201 SIKES HALL	CLEMSON	SC	29634	PICKENS	USA	Allergy and Infectious Diseases Research	000	1	12/10/2019	NEW	$381,090
														Subtotal = $381,090

Grand Total All Awards = $1,845,973

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Regulation of the physiology and function of the digestive vacuole in Toxoplasma gondii

Award Number: R01AI143707

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/10/2019

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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