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Defining the Inflammation and Immunity Transcriptome in Severe Malarial Anemia for Immunotherapeutic Discovery

Award Number: R01AI130473
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY Despite advances in global health, malaria infects 212M and kills 429,000 people annually. Lack of effective vaccines and emergence of drug-resistant strains makes new therapeutic approaches essential. Childhood mortality rates in children <36 months remain exceedingly high in holoendemic Plasmodium falciparum transmission regions such as Siaya, Kenya, due to severe malarial anemia [SMA, hemoglobin (Hb)<5.0 g/dL]. Over the last 14 years, at our state-of-the-art clinical research facilities in Siaya, we focused on how innate immunity and co-morbidities influence clinical outcomes in childhood malaria. Over a three-year follow-up period, we found that 93% of the children had malaria, and 22.7% developed SMA. To identify the most significant pathways that discriminate SMA from milder forms of disease, we spent the last several years using a combination of global genomic approaches to create a convergent model for identification of disease signatures. These studies demonstrated that immune response genes are the strongest predictors for SMA, thus, narrowing the search from the entire genome to pathways involved in the host-immune response. Based on these findings and recent preliminary data, we propose to use targeted RNAseq with a platform that contains of 500 immune response genes (innate and adaptive immunity) which have not been concomitantly explored in malaria. Since our findings demonstrate that the immune response to P. falciparum drives adverse clinical outcomes for several weeks, even after clearance of the parasite, malarial anemia is an ideal candidate for immunotherapy. Thus, the overall goal of the project is to identify critical gene pathways within the transcriptome that mediate disease severity and then target these specific genes with compounds that elicit expression profiles witnessed in children with milder forms of disease. To achieve this goal, we will complete the following specific aims: 1) Determine how changing temporal dynamics of gene pathways in the Malarial Immunity Transcriptome promote SMA during acute disease; 2) Determine how changes in gene pathways in the Malarial Immunity Transcriptome mediate malarial severity throughout the development of naturally- acquired immunity; and 3) Identify immunotherapeutic targets in the Malarial Immunity Transcriptome that can be used to reduce malaria disease severity and improve clinical outcomes in future trials. To successfully complete these aims, we will determine how host and parasitic expression profiles impact on acute disease over 14 days (cohort 1) and validate these findings in a longitudinal birth cohort (cohort 2) during the child's 1st episode of acute malaria. We will also determine the impact of changing host and parasite temporal expression profiles on the development of naturally-acquired immunity over 36 months (cohort 2). Ex vivo samples from the two cohorts will be used to test the effect of immunotherapeutic compounds on host expression profiles. Accomplishing these goals will have broad reaching translational implications for: (1) identifying at-risk groups, and (2) prioritizing compounds that can be used to improve clinical outcomes in future immunotherapy trials.


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 = $0 )
2024	2022	UNIVERSITY OF NEW MEXICO	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Allergy and Infectious Diseases Research	000	5	12/4/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $703,880 )
2022	2022	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Allergy and Infectious Diseases Research	000	5	12/21/2021	NON-COMPETING CONTINUATION	$703,880
														Subtotal = $703,880

Issue Date FY: 2021 ( Subtotal = $707,737 )
2021	2021	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Allergy and Infectious Diseases Research	000	4	11/25/2020	NON-COMPETING CONTINUATION	$707,737
														Subtotal = $707,737

Issue Date FY: 2020 ( Subtotal = $711,525 )
2020	2020	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Allergy and Infectious Diseases Research	000	3	1/7/2020	NON-COMPETING CONTINUATION	$711,525
														Subtotal = $711,525

Issue Date FY: 2019 ( Subtotal = $716,070 )
2019	2019	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Allergy and Infectious Diseases Research	000	2	12/12/2018	NON-COMPETING CONTINUATION	$716,070
														Subtotal = $716,070

Issue Date FY: 2018 ( Subtotal = $773,738 )
2018	2018	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Allergy and Infectious Diseases Research	000	1	1/18/2018	NEW	$773,738
														Subtotal = $773,738

Grand Total All Awards = $3,612,950

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Defining the Inflammation and Immunity Transcriptome in Severe Malarial Anemia for Immunotherapeutic Discovery

Award Number: R01AI130473

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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