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Defining neuron-Toxoplasma gondii interactions that mediate CNS toxoplasmosis

Award Number: R01NS095994
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2016
PERIOD OF PERFORMANCE END DATE: 02/28/2022

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Defining neuron-Toxoplasma gondii interactions that mediate CNS toxoplasmosis - DESCRIPTION (provided by applicant): Toxoplasma gondii's tropism for the CNS underlies the symptomatic disease it causes in developing fetuses, the immunocompromised, and, occasionally, the immunocompetent. As an intracellular parasite, Toxoplasma's ability to co-opt host cell function determines both the parasite's survival and its effects on the host. What is known about the Toxoplasma-host cell interaction comes primarily from in vitro studies in fibroblasts and immune cells. These studies have revealed that Toxoplasma commandeers host cell functions in part through the injection of effector proteins and that these proteins target boh universal and host-cell-specific pathways. While these studies established much about Toxoplasma-host cell biology, they will have missed host cell pathways specific to the CNS or only triggered during in vivo infection. These limitations are particularly relevant to the CNS, which is composed of multiple interacting cells types that maintain a baseline anti-inflammatory state. Given the vital nature of the CNS- Toxoplasma interface to clinical disease, understanding the CNS-specific effects of Toxoplasma is essential to eventually preventing symptomatic neurologic disease. To this end, we recently engineered Toxoplasma strains that inject Cre recombinase into host cells concomitantly with the effector proteins. By using these parasites to infect mice that express a green fluorescent protein only after Cre-mediated recombination, we are able to permanently identify and profile CNS cells injected with Toxoplasma effector proteins. Substantial preliminary data from this model strongly suggests that, contrary to existing dogma, Toxoplasma primarily interacts with neurons in vivo, which means that neurons are the major parenchymal CNS cell directly manipulated by Toxoplasma. The goal of this proposal is to determine how the neuron-Toxoplasma interface drives the establishment and outcomes of CNS infection. To this end, we will use our new mouse model in combination with two genetically divergent strains of Toxoplasma that cause different CNS outcomes and that we have engineered to inject Cre. Specifically, using cut- ting edge CNS imaging techniques that we have developed, we will determine if these Toxoplasma strains cause distinct CNS outcomes by infecting different CNS regions or co-opting different neuron subtypes (Aim 1). Additionally, to determine if these strain-specific CNS effects are secondary to differential manipulation of neurons, we will isolate and transcriptionally profile these Toxoplasma-injected neurons (Aim 2). The successful completion of this research will provide the first mechanistic insights into how neuron-Toxoplasma interactions drive CNS disease. Ultimately, such insights will offer us new avenues for developing CNS-specific or even strain-specific therapies that improve the outcomes of CNS disease.


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 = -$11,585 )
2022	2020	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	8/9/2022	NON-COMPETING CONTINUATION	-$11,585
														Subtotal = -$11,585

Issue Date FY: 2020 ( Subtotal = $329,930 )
2020	2020	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	2/27/2020	NON-COMPETING CONTINUATION	$329,930
														Subtotal = $329,930

Issue Date FY: 2019 ( Subtotal = $418,090 )
2019	2019	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	2/20/2019	NON-COMPETING CONTINUATION	$351,687
2019	2019	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	4	3/6/2019	NON-COMPETING CONTINUATION	$66,403
2019	2017	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	3/6/2019	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $418,090

Issue Date FY: 2018 ( Subtotal = $460,620 )
2018	2018	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	3/7/2018	NON-COMPETING CONTINUATION	$59,748
2018	2018	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	2/5/2018	NON-COMPETING CONTINUATION	$354,808
2018	2018	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	3	3/12/2018	NON-COMPETING CONTINUATION	$0
2018	2018	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	3	6/22/2018	NON-COMPETING CONTINUATION	$46,064
														Subtotal = $460,620

Issue Date FY: 2017 ( Subtotal = $455,794 )
2017	2017	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	2	7/13/2017	NON-COMPETING CONTINUATION	$39,521
2017	2017	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	5/12/2017	SUPPLEMENT FOR EXPANSION	$60,595
2017	2017	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	2/13/2017	NON-COMPETING CONTINUATION	$355,678
														Subtotal = $455,794

Issue Date FY: 2016 ( Subtotal = $373,562 )
2016	2016	UNIVERSITY OF ARIZONA	POST OFFICE BOX 3308	TUCSON	AZ	85722		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	7/14/2016	SUPPLEMENT FOR EXPANSION	$43,512
2016	2016	UNIVERSITY OF ARIZONA	POST OFFICE BOX 3308	TUCSON	AZ	85722		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	2/29/2016	NEW	$330,050
														Subtotal = $373,562

Grand Total All Awards = $2,026,411

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Defining neuron-Toxoplasma gondii interactions that mediate CNS toxoplasmosis

Award Number: R01NS095994

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2016

PERIOD OF PERFORMANCE END DATE: 02/28/2022

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