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Adhesive Interactions in Severe Malaria

Award Number: R01AI114766
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: 06/24/2015
PERIOD OF PERFORMANCE END DATE: 05/31/2022

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Adhesive Interactions in Severe Malaria - DESCRIPTION (provided by applicant): Cerebral malaria is a deadly complication of Plasmodium falciparum infection that is associated with the massive accumulation of infected erythrocytes in cerebral microvasculature. Parasite binding is mediated by the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family. Recently, we discovered that parasites expressing DC8 and DC13 PfEMP1 are associated with cerebral malaria and showed that they bind to endothelial protein C receptor (EPCR) via the cysteine-rich interdomain region (CIDR) domain in PfEMP1. The finding that DC8 and DC13 PfEMP1 bind EPCR has important implications for cerebral malaria pathogenesis. EPCR is a receptor for activated protein C and plays a key role in regulating coagulation and endothelial barrier properties. These findings suggest there may be causal links between parasite cytoadhesion and microvascular pathology, such as a blockade of the protein C-EPCR interaction by DC8 or DC13-expressing infected erythrocytes. While this mechanism provides an appealing explanation for many of the pathophysiological correlates of cerebral malaria, a number of critical questions remain unanswered including to what extent DC8 and DC13 PfEMP1 inhibit EPCR function and identifying the combination of host receptors mediating cerebral binding. In this project, we will: 1. Determine if EPCR-binding parasites inhibit the protein C-EPCR interaction, 2. Determine if EPCR-binding parasites affect the cytoprotective and pro-barrier function of EPCR on endothelial cells and 3. Determine the combination of host receptors that act in concert with EPCR to mediate high affinity binding of DC8 variants to brain endothelial cells. This project will characterize the molecular mechanisms by which P. falciparum-infected erythrocytes adhere to brain endothelial cells, shed light on the pathogenic mechanisms associated with cerebral malaria, and may suggest anti-adhesive strategies or new treatment options to improve cerebral malaria outcomes.


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: 2023 ( Subtotal = $0 )
2023	2019	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	6	7/21/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2017	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	3	9/23/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2019	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	6	5/28/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $547,036 )
2019	2019	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	005	6	6/5/2019	NON-COMPETING CONTINUATION	$559,411
2019	2018	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	004	5	4/16/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$391,857
2019	2018	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	001	5	1/10/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$419,982
2019	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	003	4	4/16/2019	NON-COMPETING CONTINUATION	-$154,930
2019	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	4	1/10/2019	NON-COMPETING CONTINUATION	-$432,357
2019	2017	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	002	3	4/16/2019	NON-COMPETING CONTINUATION	-$236,927
														Subtotal = $547,036

Issue Date FY: 2018 ( Subtotal = $587,287 )
2018	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	4	5/8/2018	NON-COMPETING CONTINUATION	$587,287
														Subtotal = $587,287

Issue Date FY: 2017 ( Subtotal = $575,941 )
2017	2017	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	3	5/31/2017	NON-COMPETING CONTINUATION	$575,941
														Subtotal = $575,941

Issue Date FY: 2016 ( Subtotal = $594,841 )
2016	2016	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N, STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	2	5/20/2016	NON-COMPETING CONTINUATION	$594,841
														Subtotal = $594,841

Issue Date FY: 2015 ( Subtotal = $581,593 )
2015	2015	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N, STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	001	1	8/20/2015	NEW	$88,488
2015	2015	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N, STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	1	6/11/2015	NEW	$493,105
														Subtotal = $581,593

Grand Total All Awards = $2,886,698

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Adhesive Interactions in Severe Malaria

Award Number: R01AI114766

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: 06/24/2015

PERIOD OF PERFORMANCE END DATE: 05/31/2022

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