The majority of malaria-associated deaths occur in children less than 5 years of age and severe malaria accounts for up to 90% of such deaths. We are interested in dissecting why some children develop either one of the severe malarial syndromes or the uncomplicated Malaria (UM). We studied a total of 1,622 plasma and 519 DNA samples from our pediatric Nigerian cohort. By monitoring and comparing the differences in the plasma proteome in the UM group to each of the severe syndromes at both onset and through convalescence we found that congenitally low plasma Haptoglobin (Hp), low/stable plasma level of sCD163, sub-optimal plasma Hemopexin (HPx) level and low plasma clusterin (CLU) levels could be put forward as predictors of acute/insidious onset of severe malarial anaemia (SMA) and Cerebral Malaria (CM). We show that low plasma CLU is a very specific marker of CM at acute onset and propose a mechanism through which high CLU levels can protect from CM. We also propose that circulatory HPx level is useful as both diagnostic and prognostic biomarkers of severe malaria as its level varies among the severe malaria forms at acute onset and also increases sensitively with response to treatment in all the malaria groups.
We show that Hp phenotypes could be linked to the pathological differences that underlie the acute onset of UM, severe malaria and disease progression among subjects: Hp phenotypes seem to modulate response to malarial infection and might be responsible for contradictory reports on the pathophysiology of severe malaria. We also show for the first time that Hp gene sequence variants/deletions at sites in both the distal and proximal upstream region are significantly associated with protection from and susceptibility to malaria, whether or not they are associated with plasma Hp levels
