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Genomic Studies Presented at ASHG Explore Malaria Responses in West African Children

NEW YORK – Research teams tracking malaria infections in West African children over time are turning to metabolomics, RNA sequencing, and other genomic approaches to explore interactions between the host and the Plasmodium falciparum parasite that may contribute to variable malaria responses between individuals.

As part of a session on genomics in Africa at the American Society of Human Genetics annual meeting, held virtually this week, New York University Abu Dhabi's Youssef Idaghdour shared findings from an integrated host and parasite genetic, transcriptomic, and metabolomic analysis of pre- and post-infection blood serum samples. His group studied children with Gouin ancestry in Burkina Faso, as well as children with Fulani ancestry from West Africa, who are thought to have reduced susceptibility to malaria.

Idaghdour noted that malaria infections are marked by an interplay between parasite, host, and environmental factors, with Plasmodium parasites taking over some metabolic processes in host cells.

"Knowledge of these interactions in vivo is quite limited in the context of malaria, particularly in the case of children — the group most affected by the infection," he explained.

Using liquid chromatography-tandem mass spectrometry on samples from 100 children before and after Plasmodium infection, the team identified hundreds of metabolites, including steroids, originating in the host or parasite that had distinct profiles during the process of infection.

The results hinted that endogenous steroid production in particular may dampen certain immune responses in infected children — results backed up by bulk RNA sequence data on samples from three dozen of the children pre- and post-infection, as well as related cell line experiments.

In children with Fulani ancestry, Idaghdour reported, steroid production appeared to dip rather than rise and lymphocyte immune cell counts remain more stable, perhaps contributing to the stronger immune responses to P. falciparum that have been described in this population.

"These results support the hypothesis that immunosuppression is likely taking place in the Gouin ethnic group, while it's not taking place in the Fulani children," he said.

Findings from the metabolomic arm of the study were reported in Nature Metabolism in July. But the investigators have also generated additional genotyping, methylation, RNA sequencing, microRNA sequence, lipidomic, and single-cell data on blood or peripheral blood mononuclear cell (PBMC) samples from the participants as part of their ongoing integrative genomic study.

During the same conference session, New York University Abu Dhabi researcher Odmaa Bayaraa presented findings from a transcriptomic and genomic study co-authored by Idaghdour, which focused on 150 children from the Gouin ethnic group in Burkina Faso.

"Before-infection sampling was conducted in May and during-infection sampling in June, in the rainy season when transmission rates were relatively higher," Bayaraa explained, noting that matched pre- and post-P. falciparum infection samples were available for 32 of the children.

With single-cell RNA sequencing data for nearly 80,200 individual PBMCs collected before or during infection, along with available whole-genome sequencing and bulk RNA sequencing data for a larger group of participants, the team highlighted blood cell types and subtypes with altered representation and gene expression patterns in response to P. falciparum.

For example, the team saw a marked decline in cell density during infection, together with transcriptional changes, Bayaraa said, though the findings pointed to variable responses from one individual to the next, both in samples collected prior to and after infection.

By combining gene expression and genetic profiles, meanwhile, the investigators characterized cell type-specific expression quantitative trait loci, or eQTL, in single cells from half a dozen cell types that were or were not exposed to P. falciparum infection.

"Single-cell RNA-seq eQTL analysis revealed cell type-specific eQTLs and genome-wide significant genotype-by-infection interaction effects implicating key immune genes," Bayaraa and her co-authors wrote in an abstract accompanying the ASHG presentation. "These results provide the first genome-wide picture of host in vivo regulatory variation events in malaria at the single-cell level and highlight the implication of regulatory interaction effects in modulating host immune response in vivo."

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