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Control of parasite invasion by a microneme protein complex conserved in Apicomplexans

Award Number: R01AI144369
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: 12/01/2019
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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Control of parasite invasion by a microneme protein complex conserved in Apicomplexans - 7. PROJECT SUMMARY/ABSTRACT Apicomplexan parasites include the etiologic agents of many widespread infections of humans and livestock, such as malaria and toxoplasmosis. These diseases are caused by destruction of the host tissues in which the parasites replicate. Because apicomplexans only replicate inside host cells, the process of invasion is critical to their survival and pathogenesis. Invasion is mediated by the release of proteins from specialized secretory organelles at the apical end of the parasite, the micronemes and rhoptries. Microneme proteins include adhesins that support parasite motility and are therefore secreted as soon as parasites emerge from replication and start migrating towards new host cells to infect. Rhoptries, by contrast, secrete their contents only upon host cell recognition once parasites have committed to invasion. Evidence suggests that the release of rhoptry contents depends on the prior secretion of microneme proteins; however, the molecular events that link these two processes are unknown. Based on a genome-wide screen in the model apicomplexan Toxoplasma gondii, our lab recently identified a conserved microneme protein necessary for invasion of human cells, which we named CLAMP. Our preliminary studies show that CLAMP is necessary for rhoptry secretion and stably associates with two microneme proteins: SPATR, which was previously implicated in invasion, and an uncharacterized protein we call CLIP. We hypothesize that these interactions represent a novel invasion complex necessary for rhoptry protein secretion. Our first aim is to compare the functions of CLAMP, SPATR, and CLIP; investigate how they oligomerize; and elucidate the relationship between complex formation and rhoptry secretion. In our second aim, we will identify and characterize host and parasite proteins that interact with the CLAMP invasion complex. Finally, our third aim will take an unbiased look at the host cell factors that stimulate rhoptry protein secretion, which may intersect with the CLAMP complex to regulate this key step in apicomplexan invasion. Based on the conservation of the parasite proteins involved, we expect that the principles uncovered will be generalizable to the phylum and broadly inform our understanding of these infectious agents.


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 = $487,500 )
2024	2024	WHITEHEAD INSTITUTE FOR BIOMEDICAL RESEARCH	455 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Allergy and Infectious Diseases Research	001	5	5/16/2024	NON-COMPETING CONTINUATION	$48,750
2024	2024	WHITEHEAD INSTITUTE FOR BIOMEDICAL RESEARCH	455 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	5	11/22/2023	NON-COMPETING CONTINUATION	$438,750
														Subtotal = $487,500

Issue Date FY: 2023 ( Subtotal = $487,500 )
2023	2023	WHITEHEAD INSTITUTE FOR BIOMEDICAL RESEARCH	455 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	4	11/8/2022	NON-COMPETING CONTINUATION	$487,500
														Subtotal = $487,500

Issue Date FY: 2022 ( Subtotal = $487,500 )
2022	2022	WHITEHEAD INSTITUTE FOR BIOMEDICAL RESEARCH	455 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	3	11/23/2021	NON-COMPETING CONTINUATION	$487,500
														Subtotal = $487,500

Issue Date FY: 2021 ( Subtotal = $487,500 )
2021	2021	WHITEHEAD INSTITUTE FOR BIOMEDICAL RESEARCH	455 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	2	11/13/2020	NON-COMPETING CONTINUATION	$487,500
														Subtotal = $487,500

Issue Date FY: 2020 ( Subtotal = $487,500 )
2020	2020	WHITEHEAD INSTITUTE FOR BIOMEDICAL RESEARCH	455 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	1	11/26/2019	NEW	$487,500
														Subtotal = $487,500

Grand Total All Awards = $2,437,500

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Control of parasite invasion by a microneme protein complex conserved in Apicomplexans

Award Number: R01AI144369

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: 12/01/2019

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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