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London School of Hygiene & Tropical Medicine Malaria Centre

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Integrated pathogen load and dual transcriptome analysis of systemic host-pathogen interactions in severe malaria

Journal: Science Translational Medicine 

Authors: Hyun Jae Lee, Athina Georgiadou, Michael Walther, Davis Nwakanma, Lindsay B. Stewart, Michael Levin, Thomas D. Otto, David J. Conway, Lachlan J. Coin, Aubrey J. Cunnington

The pathogenesis of infectious diseases depends on the interaction of host and pathogen. In Plasmodium falciparum malaria, host and parasite processes can be assessed by dual RNA-sequencing of blood from infected patients. Here we performed dual transcriptome analyses on samples from 46 malaria-infected Gambian children to reveal mechanisms driving the systemic pathophysiology of severe malaria. 

We report hundreds of human and parasite genes differentially expressed between severe and uncomplicated malaria, with distinct profiles associated with coma, hyperlactatemia, and thrombocytopenia. Co-expression analyses revealed interactions between human and P. falciparum, with prominent co-regulation of translation genes in severe malaria between host and parasite. Multivariate analyses suggested that increased expression of granulopoiesis and interferon-γ related genes, together with inadequate suppression of type-1 interferon signalling, best explained severity of infection. These findings provide a framework for understanding the contributions of host and parasite to the pathogenesis of severe malaria and identifying targets for adjunctive therapy.