Abstract
Clearance of non-infected red blood cells (nRBCs) is one of the main components of anemia associated with Plasmodium vivax malaria. Recently, we have shown that anemic patients with P. vivax infection had elevated levels of anti-RBCs antibodies, which could enhance in vitro phagocytosis of nRBCs and decrease their deformability. Using immunoproteomics, here we characterized erythrocytic antigens that are differentially recognized by autoantibodies from anemic and non-anemic patients with acute vivax malaria. Protein spots exclusively recognized by anemic P. vivax-infected patients were identified by mass spectrometry revealing band 3 and spectrin as the main targets. To confirm this finding, antibody responses against these specific proteins were assessed by ELISA. In addition, an inverse association between hemoglobin and anti-band 3 or anti-spectrin antibodies levels was found. Anemic patients had higher levels of IgG against both band 3 and spectrin than the non-anemic ones. To determine if these autoantibodies were elicited because of molecular mimicry, we used in silico analysis and identified P. vivax proteins that share homology with human RBC proteins such as spectrin, suggesting that infection drives autoimmune responses. These findings suggest that band 3 and spectrin are potential targets of autoantibodies that may be relevant for P. vivax malaria-associated anemia.
Highlights
Plasmodium vivax accounts for a sizable portion of the global malaria burden and is being increasingly associated to fatal outcomes with anemia as one of the major complications[1,2] in young children[1,2,3,4] and pregnant women[5,6]
Several reasons have been suggested to explain the removal of nRBC8, including impaired RBC production through dyserythropoiesis or bone marrow insufficiency[9], exposition of erythrocytes to oxidative stress triggered by parasite rupture or host immune responses[10,11], and mechanical ex vivo destruction of non-infected red blood cells, as it has been demonstrated using a splenic sinusoid model[12], in addition to other mechanisms that may be relevant to P. vivax-associated anemia
To determine whether IgG antibodies recognizing nRBC antigens are increased during acute P. vivax malaria, median levels of such immunoglobulins were assessed by ELISA in plasma from patients with patent P. vivax infection presenting (n = 24) or not (n = 24) anemia, as well as in plasma from healthy individuals never exposed to malaria (n = 8)
Summary
Plasmodium vivax accounts for a sizable portion of the global malaria burden and is being increasingly associated to fatal outcomes with anemia as one of the major complications[1,2] in young children[1,2,3,4] and pregnant women[5,6]. In P. falciparum infections, one of the causes underlying malarial anemia is the augmented removal of nRBCs possibly boosted by increased levels of self-antibodies against nRBCs proteins[13,14,15]. Evidences in this line are given by studies that have shown an inverse association between hemoglobin levels and anti-phosphatidylserine antibodies in humans with late post-anemia due to P. falciparum infection[14]. Our group recently demonstrated that in vitro erythrophagocytosis of nRBCs was mediated by anti-erythrocyte antibodies purified from anemic patients with vivax malaria, possibly through a decrease in cell deformability[19]. We confirmed the reactivity of those antigens using ELISA and investigated the possible contribution of molecular mimicry to vivax malaria associated-anemia by searching for P. vivax proteins that share homology with human RBCs
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