Abstract
BackgroundThe factors involved in the progression from Plasmodium falciparum infection to severe malaria (SM) are still incompletely understood. Altered antibody and cellular immunity against P. falciparum might contribute to increase the risk of developing SM.MethodsTo identify immune responses associated with SM, a sex- and age-matched case–control study was carried out in 134 Mozambican children with SM (cerebral malaria, severe anaemia, acidosis and/or respiratory distress, prostration, hypoglycaemia, multiple seizures) or uncomplicated malaria (UM). IgG and IgM against P. falciparum lysate, merozoite antigens (MSP-119, AMA-1 and EBA-175), a Duffy binding like (DBL)-α rosetting domain and antigens on the surface of infected erythrocytes were measured by ELISA or flow cytometry. Plasma concentrations of IL-12p70, IL-2, IFN-γ, IL-4, IL-5, IL-10, IL-8, IL-6, IL-1β, TNF, TNF-β and TGF-β1 were measured using fluorescent bead immunoassays. Data was analysed using McNemar’s and Signtest.ResultsCompared to UM, matched children with SM had reduced levels of IgG against DBLα (P < 0.001), IgM against MSP-119 (P = 0.050) and AMA-1 (P = 0.047), TGF-β1 (P <0.001) and IL-12 (P = 0.039). In addition, levels of IgG against P. falciparum lysate and IL-6 concentrations were increased (P = 0.004 and P = 0.047, respectively). Anti-DBLα IgG was the only antibody response associated to reduced parasite densities in a multivariate regression model (P = 0.026).ConclusionsThe lower levels of antibodies found in children with SM compared to children with UM were not attributable to lower exposure to P. falciparum in the SM group. IgM against P. falciparum and specific IgG against a rosetting PfEMP1 domain may play a role in the control of SM, whereas an imbalanced pro-inflammatory cytokine response may exacerbate the severity of infection. A high overlap in symptoms together with a limited sample size of different SM clinical groups reduced the power to identify immunological correlates for particular forms of SM.
Highlights
The factors involved in the progression from Plasmodium falciparum infection to severe malaria (SM) are still incompletely understood
This study reports a reduction of immunoglobulin M (IgM) responses to blood stage antigens in children with SM compared to uncomplicated malaria (UM), in agreement with findings from previous studies
This study suggests that children with SM may have an immature immune system typical of early childhood, consisting in a greater dependence on innate immune responses for protection against infections [59], lower Th1-polarizing cytokine responses (i.e. IL-12) [60,61] and a bias of Toll-Like receptor-mediated responses towards acute phase (i.e. IL-1β and IL-6) and IL-10 responses [60]
Summary
The factors involved in the progression from Plasmodium falciparum infection to severe malaria (SM) are still incompletely understood. Altered antibody and cellular immunity against P. falciparum might contribute to increase the risk of developing SM. In countries endemic for Plasmodium falciparum, severe malaria (SM) was responsible for approximately 0.7 million deaths in 2010, predominantly children under five years of age [1]. Progression from infection to severe clinical malaria is probably multi-factorial, including sequestration of infected erythrocytes (IEs) in vital organs and mechanical obstruction of blood flow, limited malaria-specific antibody immunity and deregulated inflammatory responses to P. falciparum [2]. Several studies have reported associations between antibody responses and risk of SM in young children [7,8,9,10,11,12]. The role of immunoglobulin M (IgM) antibodies in children with SM has been much less explored [9,12], reduced IgM responses have been observed in adults with CM [13,14]
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