Transcriptome-based analysis of blood samples reveals elevation of DNA damage response, neutrophil degranulation, cancer and neurodegenerative pathways in Plasmodium falciparum patients

Akua A Karikari,Wasco Wruck,James Adjaye

doi:10.1186/s12936-021-03918-5

Akua A Karikari, Wasco Wruck + Show 1 more

Open Access

https://doi.org/10.1186/s12936-021-03918-5

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Abstract

BackgroundMalaria caused by Plasmodium falciparum results in severe complications including cerebral malaria (CM) especially in children. While the majority of falciparum malaria survivors make a full recovery, there are reports of some patients ending up with neurological sequelae or cognitive deficit.MethodsAn analysis of pooled transcriptome data of whole blood samples derived from two studies involving various P. falciparum infections, comprising mild malaria (MM), non-cerebral severe malaria (NCM) and CM was performed. Pathways and gene ontologies (GOs) elevated in the distinct P. falciparum infections were determined.ResultsIn all, 2876 genes were expressed in common between the 3 forms of falciparum malaria, with CM having the least number of expressed genes. In contrast to other research findings, the analysis from this study showed MM share similar biological processes with cancer and neurodegenerative diseases, NCM is associated with drug resistance and glutathione metabolism and CM is correlated with endocannabinoid signalling and non-alcoholic fatty liver disease (NAFLD). GO revealed the terms biogenesis, DNA damage response and IL-10 production in MM, down-regulation of cytoskeletal organization and amyloid-beta clearance in NCM and aberrant signalling, neutrophil degranulation and gene repression in CM. Differential gene expression analysis between CM and NCM showed the up-regulation of neutrophil activation and response to herbicides, while regulation of axon diameter was down-regulated in CM.ConclusionsResults from this study reveal that P. falciparum-mediated inflammatory and cellular stress mechanisms may impair brain function in MM, NCM and CM. However, the neurological deficits predominantly reported in CM cases could be attributed to the down-regulation of various genes involved in cellular function through transcriptional repression, axonal dysfunction, dysregulation of signalling pathways and neurodegeneration. It is anticipated that the data from this study, might form the basis for future hypothesis-driven malaria research.

Highlights

Malaria caused by Plasmodium falciparum results in severe complications including cerebral malaria (CM) especially in children
The severity of falciparum malaria correlates with the release of HMZ, which can be incorporated into membranes and diffuse through the blood brain barrier (BBB) [3, 13,14,15]
Germane to HMZ pathology is the production of reactive oxygen species (ROS), which is implicated in oxidative macromolecular damage, inflammatory response, endoplasmic reticulum (ER) stress and apoptosis [18,19,20,21,22]

Summary

Introduction

Malaria caused by Plasmodium falciparum results in severe complications including cerebral malaria (CM) especially in children. The disease is most severe in Africa, where the World Health Organization (WHO) malaria report in 2020 revealed that the region accounts for 94% of malaria cases and deaths universally [1]. Of the five human parasite species, Plasmodium falciparum and Plasmodium vivax are the most common cause of severe malaria [2]. The severity of falciparum malaria correlates with the release of HMZ, which can be incorporated into membranes and diffuse through the blood brain barrier (BBB) [3, 13,14,15]. Though P. falciparum does not invade the brain parenchyma, toxic HMZ crosses the BBB, causing injuries to neurons [16, 17]. Boldt et al found a signature of 22 differentially expressed genes related to immunopathological processes and complement regulation in the transcriptome of distinct conditions of childhood malaria including CM [30]

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