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Perturbations of host cell signaling by a complex hepatotropic pathogen

Award Number: R01AI177257
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: 04/01/2013
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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Perturbations of host cell signaling by a complex hepatotropic pathogen - ABSTRACT During Plasmodium parasite liver stage infection, parasites protect their host hepatocyte by preventing its death and exploiting host resources for growth and development. This process is imperfect, as some parasites succumb to host defenses and are eliminated by host cell death; this, in turn, elicits an immune response. This proposal is focused on the investigation of molecular mechanisms in the hepatocyte that curtail, or promote, malaria parasite infection and the immunological consequences of those outcomes. After transmission by a mosquito, Plasmodium parasites are carried by the blood stream to the liver and invade a single hepatocyte to form a liver stage. Throughout the liver stage we have shown that both apoptosis and lipid peroxide mediated death pathways curtail infection. Whether the infected cell survives or succumbs to host cell death has consequences that expand beyond the individual infection; parasites that are eliminated via hepatocyte cell death can provide potent stimuli for the subsequent immune response and the nature of the immune stimulation is partially dependent on the type of regulated cell death engaged. Indeed, we show that immune cell subsets, in particular immune cells with markers consistent with tolerogenic macrophages, sequester around the parasite during liver infection. Additionally, eliminating apoptosis, a sterile form of cell death, reduces immunity in response to whole parasite vaccination. This proposal aims to test the hypothesis that multiple forms of cell death can control Plasmodium infection and that altering the balance between sterile and inflammatory forms of cell death impacts subsequent immunity to parasite infection. To test this hypothesis, we will make extensive use of animal and technological tools. First, we will use mice with cell death pathways eliminated exclusively in hepatocytes to examine the specific role of each type of cell death in regulating wild type parasites and parasites with multiple biological deficiencies. We will use genome wide CRISPR/Cas9 screens to identify specific genetic regulators of cell death in infected cells and we will make use of a mosquito dissection robot that we have recently designed, built, and tested to perform larger, more unbiased analyses than previously possible. We will also take advantage of state-of-the-art spatial profiling approaches that facilitate the collection of proteomic and transcriptomic information in situ for Plasmodium-infected livers to examine infected cells, and the surrounding immune environment. In addition to identifying mediators of initial infection, will use these tools to ask how altered hepatocyte death primes CD8 T cell responses and informs immunity to subsequent infection. Accomplishing our aims enables altering key host factors with small- molecules that could prevent a wild-type parasite from progressing to symptomatic erythrocytic infection or eliminate infection in a way that elicits a potent immune response against subsequent challenge.


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: 2025 ( Subtotal = $663,183 )
2025	2025	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	13	2/13/2025	NON-COMPETING CONTINUATION	$663,183
														Subtotal = $663,183

Issue Date FY: 2024 ( Subtotal = $645,448 )
2024	2024	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	12	1/16/2024	NON-COMPETING CONTINUATION	$580,903
2024	2024	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	001	12	5/23/2024	NON-COMPETING CONTINUATION	$64,545
														Subtotal = $645,448

Issue Date FY: 2023 ( Subtotal = $629,962 )
2023	2023	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	11	2/23/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$629,962
														Subtotal = $629,962

Grand Total All Awards = $1,938,593

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Perturbations of host cell signaling by a complex hepatotropic pathogen

Award Number: R01AI177257

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: 04/01/2013

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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