Date Published: April 17, 2014
Publisher: Public Library of Science
Author(s): Julie Bachmann, Florence Burté, Setia Pramana, Ianina Conte, Biobele J. Brown, Adebola E. Orimadegun, Wasiu A. Ajetunmobi, Nathaniel K. Afolabi, Francis Akinkunmi, Samuel Omokhodion, Felix O. Akinbami, Wuraola A. Shokunbi, Caroline Kampf, Yudi Pawitan, Mathias Uhlén, Olugbemiro Sodeinde, Jochen M. Schwenk, Mats Wahlgren, Delmiro Fernandez-Reyes, Peter Nilsson, Kami Kim.
Systemic inflammation and sequestration of parasitized erythrocytes are central processes in the pathophysiology of severe Plasmodium falciparum childhood malaria. However, it is still not understood why some children are more at risks to develop malaria complications than others. To identify human proteins in plasma related to childhood malaria syndromes, multiplex antibody suspension bead arrays were employed. Out of the 1,015 proteins analyzed in plasma from more than 700 children, 41 differed between malaria infected children and community controls, whereas 13 discriminated uncomplicated malaria from severe malaria syndromes. Markers of oxidative stress were found related to severe malaria anemia while markers of endothelial activation, platelet adhesion and muscular damage were identified in relation to children with cerebral malaria. These findings suggest the presence of generalized vascular inflammation, vascular wall modulations, activation of endothelium and unbalanced glucose metabolism in severe malaria. The increased levels of specific muscle proteins in plasma implicate potential muscle damage and microvasculature lesions during the course of cerebral malaria.
Human malaria is a life-threatening disease causing an estimated 655,000 deaths in 2010 . Although the mortality rates have decreased during the last decade, deaths in Africa due to childhood malaria are still elevated with Plasmodium falciparum attributable to a third of the childhood deaths accounted in Nigeria . Complications may develop abruptly and may be fatal. Although the most common severe syndromes, i.e. cerebral malaria, severe malaria anemia or respiratory distress, have been widely investigated, many aspects of their pathogenesis remain elusive. Furthermore, it is yet unknown what predetermines which children are at risk of developing complications.
In order to explore the potential of the human proteins in plasma to predict disease status during malaria infections, we have conducted an extensive exploratory profiling approach using antibody suspension bead arrays (Fig. 1A). Using two different approaches for target protein selection, with 304 unique proteins in a targeted array with carefully selected proteins and 711 in a random approach, a total of 1,015 human proteins have been profiled in 719 blood samples from different patients aiming to identify and verify protein signatures in plasma associated to the severity of malaria infection (Fig. 1B).
We have here investigated the levels of human proteins circulating in plasma of children with different forms of uncomplicated or severe malaria and compared the levels with those of parasite-negative community controls. The study comprises a total of 709 plasma samples including 515 from malaria-infected children. Amongst the 1,015 host proteins studied, 41 were identified as candidates discriminating between healthy community controls and malaria patients. Protein markers of oxidative stress were found elevated in anemic individuals while markers of endothelial activation, platelet adhesion and muscle- and tissue damage were found linked to cerebral malaria. Taken together, this suggests the presence of a generalized vascular inflammation, an unbalanced glucose metabolism and deep lesions into the micro-vasculature.