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A systems genetics approach to determine factors regulating Plasmodium falciparum sporozoite infectivity

Award Number: R21AI133369
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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A systems genetics approach to determine factors regulating Plasmodium falciparum sporozoite infectivity - Malaria eradication is a global health priority that will require interventions on multiple scales. The sporozoite transmission stages infect the liver and are important targets for intervention as very few parasites successfully initiate infection of the mammalian host. Early stages of infection have typically been studied using the rodent models of malaria, and the search for infectivity-associated genes has been restricted to candidate-based approaches. The recent development of liver-chimeric humanized mouse models has made a dramatic impact on the field, now enabling sporozoite transmission and liver stage studies of Plasmodium falciparum and the implementation of genetic crosses. Therefore we propose to utilize a genetic cross, conducted in the liver-chimeric humanized mouse (FRG huHep), to create a recombinant mapping population of progeny parasites that have varying levels of sporozoite infectivity. This parasite population can be used to characterize the transcriptional regulatory network underlying infectivity using systems genetics. Our preliminary data show that two clonal recombinant progeny from a genetic cross, exhibited higher sporozoite infectivity levels than the parent NF54 laboratory strain. We will characterize the remaining parasites from this cross to determine the clonal line that is most infectious, and use this parasite to perform a back cross in the FRG huHep mouse. We will identify genetic variation associated with the measured phenotypes using quantitative trait loci (QTL) mapping. Because QTL mapping will identify large linkage blocks of DNA that contain several dozen genes that may be associated with infectivity, we will then use expression QTL (eQTL) mapping, co-expression network analysis and Bayesian network construction to systematically describe the transcriptional network regulating infectivity. This study will provide genetic and transcriptional analysis of P. falciparum sporozoites on an unprecedented level, defining the molecular processes that govern sporozoite infectivity on a global scale. Dissection of the sporozoite-infectivity associated pathways and regulatory networks can be used to identify drug and vaccine targets which specifically intervene against sporozoite infection.


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: 2021 ( Subtotal = -$12,683 )
2021	2018	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	3	11/30/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$12,683
														Subtotal = -$12,683

Issue Date FY: 2019 ( Subtotal = -$13,506 )
2019	2018	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	001	3	1/11/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$153,971
2019	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	2	1/10/2019	NON-COMPETING CONTINUATION	-$167,477
2019	2018	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	004	3	4/30/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$116,158
2019	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	003	2	4/30/2019	NON-COMPETING CONTINUATION	-$77,523
2019	2017	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	002	1	4/30/2019	NEW	-$38,635
														Subtotal = -$13,506

Issue Date FY: 2018 ( Subtotal = $245,000 )
2018	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	2	5/10/2018	NON-COMPETING CONTINUATION	$245,000
														Subtotal = $245,000

Issue Date FY: 2017 ( Subtotal = $294,000 )
2017	2017	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	1	5/31/2017	NEW	$294,000
														Subtotal = $294,000

Grand Total All Awards = $512,811

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A systems genetics approach to determine factors regulating Plasmodium falciparum sporozoite infectivity

Award Number: R21AI133369

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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