Plasmodium falciparum malaria is a major cause of morbidity and mortality and factors that determine the development of uncomplicated (UM) versus cerebral malaria (CM) are not fully understood. It is likely, however, that many different host, parasite, vectorial and circumstantial factors combine to determine the severity of each malarial illness. We showed that heterogeneity in TNF responsiveness does occur at the level of the vascular endothelial cell, a diversity that might influence the severity of the disease in patients with malaria. The main objective of this project is to decipher the different molecular mechanisms underlying the endothelial inter-individual variations in response to TNF in order to develop tools to identify patients at risks and develop new therapeutic approaches. For this, we will carry out an extensive analysis of the difference in responsiveness to TNF we described between UM (low responders) and CM (high responders) patients, using cells freshly isolated from patients admitted at Ispat General Hospital in Rourkela, India. We will analyze this variation and assess whether it is due to parameters that are """"""""extrinsic"""""""" to endothelial cells, namely their intake of TNF, or to """"""""intrinsic"""""""" parameters. This last part will be performed by a targeted comparative gene transcription analysis, coupled with a study of their associated regulatory micro (mi)RNAs between the two patient categories. We will also investigate the presence of specific single nucleotide polymorphisms (SNPs) associated with high and low responders for these genes and the frequency of identified SNPs will be measured in Indian population and in geographically diverse malaria endemic regions. Finally, we will assess the possibility of blocking/reversing the endothelial over-activation observed in high responders by using recently reported quiescence agents. The primary outcome of this project will be a better understanding of the pathology of severe malaria with a view to opening new inter-individual therapeutic approaches to dampen the endothelial over-reaction observed in CM patients.
Cerebral malaria (CM), the most severe complication of Plasmodium falciparum infection, is often fatal and represents a major public health burden. Our recent results show that patients who develop CM exhibit an over-reaction of their brain endothelium to systemic inflammation, which is not observed in patients who develop uncomplicated malaria. We aim to investigate the potential factors leading to this over-reaction and to determine whether the phenomenon can be blocked or reversed.
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