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Translation initiation factors driving persistence of Toxoplasma gondii bradyzoites in neurons

Award Number: R01AI172752
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 The protozoan parasite Toxoplasma gondii can cause recurring opportunistic infections due to its ability to persist as a latent form (bradyzoite) within patients. There is no treatment that targets bradyzoite cysts, which reconvert into the destructive proliferative stage (tachyzoites) in the immune compromised. Patients suffering from reactivated toxoplasmosis frequently present with life-threatening neurological problems, underscoring the significance of bradyzoite cysts in the brain. A better understanding of the mechanisms that drive the development of bradyzoites in neurons is necessary to devise new therapies that prevent their formation and persistence. To address this need, we developed a novel model of spontaneous tissue cyst formation in neurons using Lund human mesencephalic (LUHMES) cells. We will use this innovative system to determine the mechanisms underlying the changes in protein synthesis that are required for bradyzoite formation. Based on our previous collaborative work, we hypothesize that translation initiation factors coordinate changes in 5’-leader sequences of key mRNAs, resulting in changes in protein synthesis that induce conversion to bradyzoites. Translation begins with the binding of an eIF4F complex to the 5’-cap, which then recruits eIF2, which carries Met-tRNA. We previously showed TgIF2 is phosphorylated during bradyzoite conversion, which lowers its abundance and can alter start codon selection. Aim 1 will determine how TgIF2 becomes phosphorylated and which mRNAs are preferentially translated during spontaneous bradyzoite conversion in neurons. Our RiboSeq approach will reveal areas within 5’-leaders that regulate translation, such as upstream open reading frames (uORFs) or secondary structures, the latter of which will be identified by generating the first RNA “structurome” for Toxoplasma in Aim 2. As these structures are resolved by helicase activity of eIF4F, Aim 2 will also delineate the functions of the multiple TgIF4F complexes we have uncovered in the parasites. Together, these studies will determine how cellular signals coordinate translation initiation factors to reprogram the translatome to trigger the spontaneous formation of bradyzoites in human neurons. Completion of this study will have a sustained high impact on the field by providing significant new insights into the complex mechanisms that Toxoplasma uses to persists in its host, which will reveal novel points for therapeutic intervention.


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 = $516,418 )
2024	2024	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Allergy and Infectious Diseases Research	000	2	11/13/2023	NON-COMPETING CONTINUATION	$516,418
														Subtotal = $516,418

Issue Date FY: 2023 ( Subtotal = $573,797 )
2023	2023	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Allergy and Infectious Diseases Research	001	1	9/20/2023	NEW	$114,759
2023	2023	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Allergy and Infectious Diseases Research	000	1	12/8/2022	NEW	$459,038
														Subtotal = $573,797

Grand Total All Awards = $1,090,215

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Translation initiation factors driving persistence of Toxoplasma gondii bradyzoites in neurons

Award Number: R01AI172752

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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