Abstract
This study was conducted to analyze alterations in the human serum proteome as a consequence of infection by malaria parasites Plasmodium falciparum and P. vivax to obtain mechanistic insights about disease pathogenesis, host immune response, and identification of potential protein markers. Serum samples from patients diagnosed with falciparum malaria (FM) (n = 20), vivax malaria (VM) (n = 17) and healthy controls (HC) (n = 20) were investigated using multiple proteomic techniques and results were validated by employing immunoassay-based approaches. Specificity of the identified malaria related serum markers was evaluated by means of analysis of leptospirosis as a febrile control (FC). Compared to HC, 30 and 31 differentially expressed and statistically significant (p<0.05) serum proteins were identified in FM and VM respectively, and almost half (46.2%) of these proteins were commonly modulated due to both of the plasmodial infections. 13 proteins were found to be differentially expressed in FM compared to VM. Functional pathway analysis involving the identified proteins revealed the modulation of different vital physiological pathways, including acute phase response signaling, chemokine and cytokine signaling, complement cascades and blood coagulation in malaria. A panel of identified proteins consists of six candidates; serum amyloid A, hemopexin, apolipoprotein E, haptoglobin, retinol-binding protein and apolipoprotein A-I was used to build statistical sample class prediction models. By employing PLS-DA and other classification methods the clinical phenotypic classes (FM, VM, FC and HC) were predicted with over 95% prediction accuracy. Individual performance of three classifier proteins; haptoglobin, apolipoprotein A-I and retinol-binding protein in diagnosis of malaria was analyzed using receiver operating characteristic (ROC) curves. The discrimination of FM, VM, FC and HC groups on the basis of differentially expressed serum proteins demonstrates the potential of this analytical approach for the detection of malaria as well as other human diseases.
Highlights
The burden of malaria continues to worsen globally with a devastating impact on human health and corresponding impediment to economic improvement [1]
Malaria patients (FM and vivax malaria (VM)) selected for this proteomic analysis were suffering from uncomplicated, nonsevere plasmodial infections with comparable range of parasitemia
The average age of the falciparum malaria (FM) and VM patients included in this proteomic analysis was 34.2 years (SD = 10.93; range 20–53; median 35) and 32.9 years (SD = 10.76; range 20–52; median 32), respectively (Table 1)
Summary
The burden of malaria continues to worsen globally with a devastating impact on human health and corresponding impediment to economic improvement [1]. Plasmodium falciparum (Pf) infection represents the major cause of malaria associated morbidity and mortality worldwide. In order to survive within the host cells and ensure their reproduction, intracellular parasites like Plasmodium develop versatile mechanisms to exploit their host cells and induce new permeability pathways to permit the uptake of nutrients and the removal of waste products, resulting into activation of multiple host immune cascades and inflammatory responses [4]. Proteomic studies have contributed substantially to our understanding of the clinical proteome of human malaria parasites [7], profiling humoral immune responses to Plasmodium infection [8] and the malaria parasite infection-induced changes in host erythrocyte membrane proteins [9]. The findings obtained from such studies have provided better understanding of the disease pathogenesis, host-pathogen interactions and host immune response
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