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

Lee, H. J., Georgiadou, A., Walther, M., Nwakanma, D., Stewart, L. B., Levin, M., Otto, T. D. , Conway, D. J., Coin, L. J. and Cunnington, A. J. (2018) Integrated pathogen load and dual transcriptome analysis of systemic host-pathogen interactions in severe malaria. Science Translational Medicine, 10(447), eaar3619. (doi: 10.1126/scitranslmed.aar3619) (PMID:29950443)

Abstract

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. We performed dual transcriptome analyses on samples from 46 malaria-infected Gambian children to reveal mechanisms driving the systemic pathophysiology of severe malaria. Integrating these transcriptomic data with estimates of parasite load and detailed clinical information allowed consideration of potentially confounding effects due to differing leukocyte proportions in blood, parasite developmental stage, and whole-body pathogen load. We report hundreds of human and parasite genes differentially expressed between severe and uncomplicated malaria, with distinct profiles associated with coma, hyperlactatemia, and thrombocytopenia. High expression of neutrophil granule–related genes was consistently associated with all severe malaria phenotypes. We observed severity-associated variation in the expression of parasite genes, which determine cytoadhesion to vascular endothelium, rigidity of infected erythrocytes, and parasite growth rate. Up to 99% of human differential gene expression in severe malaria was driven by differences in parasite load, whereas parasite gene expression showed little association with parasite load. Coexpression 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 signaling, 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 new treatments.

• Item Type: Articles
• Additional Information: This work was funded by the UK MRC and the UK Department for International Development (DFID) under the MRC/DFID Concordat agreement and is also part of the EDCTP2 program supported by the European Union (MR/L006529/1 to A.J.C.), the European Research Council (AdG-2011-294428 to D.J.C. and L.B.S.), MRC core funding of the MRCG, and the Wellcome Trust (098051 to A.J.C.). Exeter Sequencing Service is supported by an MRC Clinical Infrastructure award (MR/M008924/1), the Wellcome Trust Institutional Strategic Support Fund (WT097835MF), a Wellcome Trust Multi-User Equipment Award (WT101650MA), and a Biotechnology and Biological Sciences Research Council Longer and Larger award (BB/ K003240/1).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Otto, Professor Thomas
• Authors: Lee, H. J., Georgiadou, A., Walther, M., Nwakanma, D., Stewart, L. B., Levin, M., Otto, T. D., Conway, D. J., Coin, L. J., and Cunnington, A. J.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Science Translational Medicine
• Publisher: American Association for the Advancement of Science
• ISSN: 1946-6234
• ISSN (Online): 1946-6242
• Copyright Holders: Copyright © 2018 The Authors
• First Published: First published in Science Translational Medicine 10(447): eaar3619
• Publisher Policy: Reproduced in accordance with the publisher copyright policy