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Dual RNA Sequencing Enables Host-Pathogen Transcriptome Analysis of Uncomplicated, Severe Malaria

NEW YORK (GenomeWeb) – Researchers have uncovered gene expression differences between uncomplicated and severe malaria, potentially providing insight into the pathogenesis of the severe form of the disease.

There are some 212 million cases of malaria worldwide each year, leading to about 429,000 deaths, mostly in sub-Saharan Africa, according to the World Health Organization. Severe malaria differs from uncomplicated malaria not only by its increased risk of death, but also by its three associated syndromes: cerebral malaria, hyperlactatemia, and severe anemia.

By simultaneously sequencing the transcriptomes of infected patients from The Gambia with either uncomplicated or severe malaria and their infecting Plasmodium falciparum parasites, an international team of researchers sought to uncover differences in gene expression in either the host or parasite linked to the more severe disease.

As the team reports in Science Translational Medicine today, it found a number of differences in gene expression between the two malaria types, but noted that the increased parasite load among the severe malaria patients drove most of the observed differences.

"These data provide a unique insight into host­pathogen interactions associated with severity of infection in humans and reveal new perspectives on the likely pathogenic mechanisms of human severe malaria," senior author Aubrey Cunnington from Imperial College, London, and her colleagues wrote in their paper.

She and her colleagues performed dual RNA sequencing on a set of whole blood samples collected from 21 Gambian children with uncomplicated malaria and 25 Gambian children with severe malaria. The samples were all obtained prior to treatment. None of the children with severe malaria experienced anemia, but they did have cerebral malaria, hyperlactatemia, or both.

From these samples, the researchers obtained a median 26.6 million human uniquely mapped reads and 9.61 million parasite uniquely mapped reads and detected the expression of more than 12,000 human genes and nearly 4,000 parasite genes. After accounting for cellular heterogeneity, the researchers reported finding 770 human genes differentially expressed between the severe and uncomplicated malaria groups, including MMP8, OLFM4, DEFA3, and ELANE, all of which encode neutrophil granule proteins. These genes are also enriched for functions involving co-translational protein targeting, cell motility, and immune response.

When they separated their severe malaria group by phenotypes, they again noted differentially expressed genes, particularly in those with both cerebral malaria and hyperlactatemia, that may reflect the increased severity of their disease. Additionally, the researchers noted differences in gene expression that correlated with other clinical features, including coma severity, hemoglobin concentration, and blood lactate levels.

Similarly, the researchers found 236 parasite genes that were differentially expressed between the severe and uncomplicated malaria groups. The most up-regulated parasite gene in severe malaria was PF3D7_1016300, which encodes a glycophorin­binding protein that affects the adhesion and rigidity of erythrocytes.

They likewise noted differences in parasite gene expression that correlated with clinical features. In combination with other findings, this suggested to the researchers that parasite gene expression could contribute to host pathophysiology.

However, the researchers also reported that much of the differences in gene expression were driven by parasite load, especially among host expression. When they adjusted their data using the soluble parasite protein PfHRP2 as a biomarker of parasite load, only 13 human genes remained significant.

By building a co-expression network of host and parasite genes, the researchers uncovered about two dozen different modules. Some of these modules were associated with disease severity, and the increased expression of granulopoiesis- and interferon-gamma-related genes combined with the insufficient suppression of type 1 interferon signaling could best account for infection severity.

The researchers also noted that their findings further suggest a role for neutrophils in severe malaria. 

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