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Proteomics Clin Appl. 2018 Jul;12(4):e1600187. doi: 10.1002/prca.201600187. Epub 2018 Feb 27.

Identification of Host-Response in Cerebral Malaria Patients Using Quantitative Proteomic Analysis.

Author information

1
Institute of Bioinformatics, International Technology Park, Bangalore, India.
2
Manipal Academy of Higher Education, Manipal, Karnataka, India.
3
Department of Neuromicrobiology, National Institute of Mental Health and Neuro Sciences, Bangalore, India.
4
Center for Systems Biology and Molecular Medicine, Yenepoya (Deemed to be University), Mangalore, India.
5
Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bangalore, India.
6
Human Brain Tissue Repository, Neurobiology Research Centre, National Institute of Mental Health and Neurosciences, Bangalore, India.

Abstract

PURPOSE:

The objective of this study was to study the altered proteome in the frontal lobe of patients with CM. Unbiased analysis of differentially abundant proteins could lead to identification of host responses against Plasmodium falciparum infection, which will aid in better understanding of the molecular mechanism of pathophysiology in CM.

EXPERIMENTAL DESIGN:

TMT-based quantitative proteomic analysis using high-resolution mass spectrometry is employed. In brief, proteins are isolated from frontal lobe samples, which are collected at autopsy from three cases of CM and three control subjects. Equal amounts of protein from each case are digested using trypsin and labeled with different TMT reagents. The pooled sample is fractionated using strong cation exchange chromatography and analyzed on Orbitrap Fusion in triplicates. For accurate quantitation of peptides, the samples are analyzed in MS3 mode. The data is searched against a combined database of human and P. falciparum proteins using Sequest and Mascot search engines.

RESULTS:

A total of 4174 proteins are identified, of which, 107 are found to be differentially abundant in the test samples with significant p-value (<0.05). Proteins associated with biological processes such as innate immune response, complement system, coagulation, and platelet activation are found to be elevated in CM cases. In contrast, proteins associated with myelination, oxidative phosphorylation, regulation of reactive oxygen species, and sodium and calcium ions transport are found to be depleted in response to CM. In addition, three P. falciparum proteins exclusively in CM brain samples are also identified.

CONCLUSIONS AND CLINICAL RELEVANCE:

The study signifies neuronal assault due to axonal injury, altered sodium and calcium ion channels, deregulated inflammation and demyelination as a part of host response to CM. Enhanced oxidative stress, repressed oxidative phosphorylation, and demyelination of axons may contribute to the severity of the disease. Further validation of these results on a large cohort can provide leads in the development of neuroprotective therapies for CM.

KEYWORDS:

Orbitrap Fusion; axonal degeneration; demyelination; oxidative stress

PMID:
29389080
DOI:
10.1002/prca.201600187
[Indexed for MEDLINE]

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