Proteomic analysis of Plasmodium falciparum induced alterations in humans from different endemic regions of India to decipher malaria pathogenesis and identify surrogate markers of severity☆
Graphical abstract
Introduction
Plasmodium falciparum infection represents the major cause of malaria-associated mortality worldwide [1]. This lethal species of malaria parasite is responsible for approximately 247 million cases and around one million deaths each year, particularly in the sub-Saharan Africa [2]. India notably contributes to the global malaria burden and has the largest population in the world at risk of malaria [3]. Moreover, due to the extremely variable malaria epidemiology in India, it is considered as an important country for malaria research [4]. Importantly, in recent years there is an increased incidence of P. falciparum compared to Plasmodium vivax malaria in different endemic regions of India [4]. Severe falciparum malaria often leads to fatal and complicated clinical manifestations including hepatic dysfunction, renal dysfunction, severe anemia, hypoglycaemia, acute respiratory distress syndrome (ARDS), cerebral manifestation, and multiple organ involvement [5].
Proteomic techniques pose tremendous potential to provide a wealth of new information to accelerate malaria research [6], [7]. In-depth analysis of the differential abundances of serum/plasma proteins during the febrile stage of the infection may help in identification of surrogate markers of infection and disease severity and can provide valuable information regarding disease pathogenesis and host immune responses [8], [9]. A few previous studies have investigated the alterations in plasma proteome profiles in cerebral falciparum malaria in children from different endemic and holoendemic regions of Africa [10], [11], [12]. However, there is a dearth of similar proteomic analysis of severe falciparum malaria in Indian populations. In an earlier study we have reported the modulations in human serum proteome and various physiological pathways in uncomplicated non-severe falciparum malaria in an adult population from India [13]. In this study, serum samples from adult severe and non-severe falciparum malaria (SFM and NSFM) patients along with healthy community controls from three different endemic regions of India were investigated using 2D-DIGE and iTRAQ-based quantitative proteomics in combination with ESI-Q-TOF and Q-Exactive mass spectrometry. Different hematological and liver function parameters were measured in malaria patients and controls for a comparative statistical analysis. Bioinformatic analysis involving the identified proteins showing altered abundance in the serum samples of falciparum malaria patients revealed the modulation of different vital physiological pathways. This study revealed potential biomarkers for monitoring disease severity of P. falciparum infection and enhanced our understanding regarding pathogenesis of falciparum malaria.
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Subject recruitment, blood collection, and serum separation
This proteomics study was conducted involving non-severe and severe falciparum malaria patients and healthy controls from three different endemic regions of India; Mumbai, Kolkata, and Bikaner. This multi-centric analysis was performed with the approval of the institutional ethics committees of Seth GS Medical College and King Edward Memorial Hospital—Mumbai, Medical College Hospital Kolkata — Kolkata, and Malaria Research Center, S.P. Medical College — Bikaner. Written informed consent was
Alterations in clinicopathological parameters in falciparum malaria patients
A total of 250 subjects (HC: n = 146, NSFM: n = 67, SFM: n = 37) were analyzed in this multi-centric study. Platelet counts and Hb levels were found to be significantly lower (p < 0.05) in malaria patients (both NSFM and SFM) as compared to the healthy controls (Table 1 and Fig. S1). Sequential decreases in those two hematological parameters were observed along with the increase in disease severity. Liver function parameters including total bilirubin, serum glutamic oxaloacetic transaminase (SGOT),
Discussion
Specific parasite and host factors, which attribute the complexity of the disease in falciparum malaria have not been clearly deciphered [18]. Hitherto, there is no clear mechanism by which we can comprehend or anticipate the severity of disease at an early stage of the infection [19]. The present study aims to contribute towards unraveling the complexity of severe falciparum malaria pathogenesis. Moreover, the intent of this study was to identify potential predictive and disease monitoring
Competing interests
The authors have declared that no competing interests exist.
Acknowledgments
The active support from Prajakta Gandhe from the Department of Clinical Pharmacology, Seth GS Medical College & KEM Hospital, Mumbai, Sumit Verma from the Medicine Department, Medical College Hospital Kolkata, and Dharmendra Rojh from the Department of Medicine, Malaria Research Center, S.P. Medical College, Bikaner in clinical sample collection process is gratefully acknowledged. We would like to thank Mayuri N. Gandhi and Manali Jadhav from the Centre for Research in Nanotechnology & Science
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This article is part of a Special Issue entitled: Proteomics in India.
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Both authors contributed equally to the preparation of this manuscript.