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Innate immune responses to malaria liver stage infection

Award Number: R01AI114699
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: 11/01/2014
PERIOD OF PERFORMANCE END DATE: 04/30/2020

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Innate immune responses to malaria liver stage infection - DESCRIPTION (provided by applicant): Plasmodium species, the etiologic agents of malaria, kill nearly 1 million people annually. They initially infect the liver as sporozoites, then they replicate as liver stages within hepatocytes to generate exoerythrocytic merozoites that initiate symptomatic blood stage infection. These preerythrocytic stages of infection are clinically silent and were thought to not provoke a significant innate immune response. Yet, recent findings from our group and collaborators have shown that preerythrocytic stages induce a pronounced innate immune response in the liver. The mechanisms by which these complex parasites induce an innate immune response and the downstream effects of these responses on parasite infection remain poorly defined. Understanding the innate immune response to this eukaryotic, intracellular pathogen is important in its own right but also a critical missing piece in the puzzl to understand the development of sterilizing adaptive immunity engendered by whole parasite immunizations. Therefore, we propose to identify which innate immune responses are activated by wild-type and attenuated Plasmodium preerythrocytic parasites and to determine how these innate immune responses influence protective adaptive immune responses. Using gene expression analysis and functional assays, we have shown that liver stage infection induces an innate immune response mediated by type I and type II interferon (IFN) signaling pathways. We have also shown that lymphocytes infiltrate the liver within days following infection and that this infiltration is strongly dependent on type I IFN (IFN-1) signaling. Furthermore, this innate response reduces the initial infection. These results indicate a link between IFN-1, lymphocyte recruitment, and subsequent innate parasite elimination. Our preliminary data also shows that this IFN-1 driven innate response shapes the adaptive immune response that is engendered by whole parasite immunizations. This we demonstrate with mice deficient in key IFN-1 signaling molecules, which surprisingly, are better protected by whole parasite immunizations. In this proposal, we intend to further delineate the generation and consequences of an IFN-mediated innate immune response to Plasmodium liver infection. In Aim 1 we will identify the host-parasite interactions that initiate this IFN-mediated innate immune response and identify the cell types in the liver that respond to IFN. In Aim 2 we will characterize cell-specific responses withi the liver following infection and identify cytokine and chemokine receptors that are necessary for innate lymphocyte infiltration. Additionally, we will evaluate the cellular mechanisms by which these innate cells eliminate liver stage parasites. Finally, in Aim 3, we will investigate how IFN-1-mediated signaling influences the development of adaptive immune responses engendered by whole parasite immunizations. Understanding the nature of the early innate immune response will reveal how a complex eukaryotic parasite engages early host immune defenses. Equally important, it will also identify innate molecular pathways to target for improvement of adaptive immune responses after vaccination that aims to protect against malaria 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 = $0 )
2021	2019	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	5	11/16/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $558,671 )
2019	2019	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	001	5	11/20/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$558,671
2019	2019	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	003	5	5/1/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$22,755
2019	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	4	11/20/2018	NON-COMPETING CONTINUATION	$0
2019	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	002	4	5/1/2019	SUPPLEMENT FOR EXPANSION	-$22,755
														Subtotal = $558,671

Issue Date FY: 2018 ( Subtotal = $544,847 )
2018	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	001	4	4/18/2018	SUPPLEMENT FOR EXPANSION	$54,847
2018	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	4	10/25/2017	NON-COMPETING CONTINUATION	$490,000
														Subtotal = $544,847

Issue Date FY: 2017 ( Subtotal = $472,500 )
2017	2017	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	3	11/1/2016	NON-COMPETING CONTINUATION	$472,500
														Subtotal = $472,500

Issue Date FY: 2016 ( Subtotal = $472,500 )
2016	2016	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N, STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	2	10/23/2015	NON-COMPETING CONTINUATION	$472,500
														Subtotal = $472,500

Issue Date FY: 2015 ( Subtotal = $472,500 )
2015	2015	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N, STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	1	10/31/2014	NEW	$472,500
														Subtotal = $472,500

Grand Total All Awards = $2,521,018

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Innate immune responses to malaria liver stage infection

Award Number: R01AI114699

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: 11/01/2014

PERIOD OF PERFORMANCE END DATE: 04/30/2020

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