Research ArticleMalaria

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

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Science Translational Medicine  27 Jun 2018:
Vol. 10, Issue 447, eaar3619
DOI: 10.1126/scitranslmed.aar3619

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Uncomplicating malaria

Plasmodium falciparum infections can progress to severe malaria, resulting in organ failure and life-threatening hematological or metabolic abnormalities. This process is sometimes thought to result from an aberrant host immune response. Lee et al. sequenced patient and parasite transcriptomes in 46 P. falciparum–infected Gambian children to better understand malarial host-pathogen interactions. They found evidence that the immune response in severe compared to uncomplicated malaria was not necessarily dysregulated but instead an expected response to high pathogen load and also implicated neutrophils in this response. This transcriptomic resource may prove useful in future studies of severe malaria and the interaction between malaria host and parasite.

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.

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