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Investigating gene regulatory networks in immune cells of children who differ in susceptibility to malaria infection using single-cell approaches

Award Number: R21AI156443
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/Abstract Malaria kills over 400,000 people annually, underscoring the need for a highly effective malaria vaccine. A better understanding of immunity to Plasmodium falciparum, the most lethal of the human malaria parasites, in naturally exposed populations can inform the rational design of more effective vaccines. However, reliable immune correlates of protection against malaria remain elusive, and relatively little is known about immunity that prevents P. falciparum infection given that sustained protection from parasitemia through natural malaria exposure is rarely observed. In our K08-funded project, we have applied systems biology approaches to a unique subset of children who remained free of P. falciparum parasitemia during a single malaria season despite intensive surveillance consisting of PCR-based screening of blood collected every 2 weeks and during sick visits as well as antibody evidence for parasite exposure during a 7-month surveillance period. This rarely observed “aparasitemic” phenotype represents the closest approximation to sterile immunity in a naturally exposed population and a unique opportunity to study host control of parasitemia. The goal of this R21 proposal is to expand on findings from our prior bulk transcriptomic analysis of whole blood obtained from these aparasitemic children using higher resolution technologies that include single-cell (sc) sequencing and multiparameter flow cytometry. We propose using scRNA-seq on baseline peripheral blood mononuclear cells (PBMCs) obtained from these children just prior to the surveillance period. When integrated with single-cell assay for transposase- accessible chromatin sequencing (scATAC-seq), which assesses genome-wide chromatin accessibility to identify “open” chromatin regions, scRNA-seq can also provide insight into the regulation of gene expression. Combining integrated single-cell approaches with functional assays can help identify gene regulatory networks within specific cell types that could serve as immune correlates of protection against malaria infection. We hypothesize that, relative to parasitemic children, aparasitemic children will demonstrate increased antigen receptor signaling within memory B and T cell subsets and enhanced P. falciparum-specific T-cell memory responses despite having decreased proportions of T cells, which may reflect trafficking of T cells out of the peripheral blood to target organs such as the liver or spleen. We will address this hypothesis with the following specific aims: 1) to determine host immune genes that are differentially regulated and expressed using integrated single-cell gene expression and chromatin accessibility profiling of PBMCs from malaria-exposed children who differ in susceptibility to P. falciparum parasitemia and 2) to identify and characterize the immunophenotypic and functional differences in PBMCs from children who differ in susceptibility to P. falciparum parasitemia. Successful completion of these aims will help identify gene signatures and gene regulatory networks relevant to malaria immunity that would form the basis of future studies aimed at elucidating the mechanisms of malaria-protective cellular responses in humans.


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: 2022 ( Subtotal = $115,218 )
2022	2022	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Allergy and Infectious Diseases Research	000	2	1/4/2022	NON-COMPETING CONTINUATION	$115,218


Issue Date FY: 2021 ( Subtotal = $317,000 )
2021	2021	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Allergy and Infectious Diseases Research	000	1	12/31/2020	NEW	$317,000


Grand Total All Awards = $432,218

Sum of Action Amount is $432,218;

Grand Total = $432,218

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Investigating gene regulatory networks in immune cells of children who differ in susceptibility to malaria infection using single-cell approaches

Award Number: R21AI156443

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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