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Secreted effectors of Toxoplasma gondii bradyzoites

Award Number: F31AI136401
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 08/01/2018
PERIOD OF PERFORMANCE END DATE: 12/31/2019

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Secreted effectors of Toxoplasma gondii bradyzoites - Project Summary/Abstract Toxoplasma gondii is an obligate intracellular parasite of the phylum Apicomplexa, a diverse group of parasites that cause various diseases in humans, such as malaria and cryptosporidiosis. T. gondii is ubiquitous worldwide, estimated to infect one-third of the human population, and is a public health concern in immunocompromised and pregnant individuals. The acute phase of infection is characterized by the tachyzoite, a fast-replicating life stage that disseminates throughout the body of a warm-blooded host. The chronic phase of infection is characterized by the bradyzoite, a slowly- replicating life stage which encysts in muscle and neural tissue via the formation of a cyst wall within a host cell. Bradyzoite biology is poorly understood; the exact composition of the cyst wall, how bradyzoites persist within host cells indefinitely, or how bradyzoites manipulate host cell function is unknown. Previous studies have demonstrated the secretion of several protein effectors by tachyzoites into their host cells across the parasitophorous vacuole, the site where parasites replicate within host cells. These include the proteins GRA16, GRA24, GRA28, and TgIST, most of which have been shown to localize to the host cell nucleus and directly interact with host cell proteins, altering host cell signaling cascades and transcription. Whether these proteins, or other unidentified secreted proteins, cross the cyst wall and enter bradyzoite infected host cells has not been previously explored. In this proposal, the first aim will be to determine the localization of GRA16, GRA24, GRA28, and TgIST after bradyzoite differentiation in vitro by epitope tagging secreted effectors at their endogenous loci and in vivo in the mouse brain using an optical clearing approach. In the second aim, the role of TgIST in bradyzoite infected cells will be investigated by knocking out and complementing the TgIST gene in the parasite and subsequently determining the inhibition of STAT1 mediated transcription in bradyzoite infected host cells. In the third aim, proximity-based biotin labeling enzymes will be fused to MYR1, a protein implicated in parasite protein export into the host cell. This will allow the identification of secreted effectors during the bradyzoite stage by mass spectrometry of biotinylated proteins following validation of positive hits. The discovery of secreted effectors by bradyzoites into host cells would challenge a paradigm in the field of Toxoplasma research, where the bradyzoite has classically been viewed as an inert but transmissible stage of the parasite. This will lead to further studies on understanding how bradyzoites alter host cell function and maintain persistency in their hosts.


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: 2022 ( Subtotal = -$7,708 )
2022	2019	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	003	3	5/6/2022	NON-COMPETING CONTINUATION	-$7,708
2022	2019	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	001	3	4/22/2022	NON-COMPETING CONTINUATION	$0
2022	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	002	2	4/22/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2022	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	1	4/22/2022	NEW	$0
														Subtotal = -$7,708

Issue Date FY: 2019 ( Subtotal = $33,090 )
2019	2019	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	002	3	7/23/2019	NON-COMPETING CONTINUATION	$33,090
2019	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	1	2/6/2019	NEW	-$26,562
2019	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	001	2	2/6/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$26,562
														Subtotal = $33,090

Issue Date FY: 2018 ( Subtotal = $49,524 )
2018	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	002	1	8/10/2018	NEW	$0
2018	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	1	7/31/2018	NEW	$44,524
2018	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	001	1	8/10/2018	NEW	$5,000
														Subtotal = $49,524

Grand Total All Awards = $74,906

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Secreted effectors of Toxoplasma gondii bradyzoites

Award Number: F31AI136401

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 08/01/2018

PERIOD OF PERFORMANCE END DATE: 12/31/2019

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