Mechanisms underlying the association between Plasmodium falciparum malaria and non-typhoidal salmonella bacteraemia in African children. (360G-Wellcome-067902_Z_02_A)

An association between Plasmodium falciparum malaria and non-typhoidal salmonella (NTS) bacteraemia in African children has long been recognised, although the underlying immunological mechanisms are poorly understood. In particular, NTS bacteraemia is associated with severe malarial anaemia (SMA) and can result in increased mortality. Erythrophagocytosis of malaria-parasitised red blood cells (PRBC) is a major cause of this anaemia and ingestion of the malaria pigment haemozoin has been shown to impair monocyte/macrophage (mo/mF) function in vitro. NTS are adapted to survive within mo/mFs and their elimination requires a TH1-cytokine response as well as activation of the oxidative burst in mo/ mFs. Recent evidence from studies of severe malaria in Gabon together with animal studies suggest that TH1-immunity is depressed in SMA. Hypotheses: 1. That SMA leads to a specific defect in the immune system resulting in increased susceptibility to NTS bacteraemia. Potential mechanisms include a) the direct effect of haemozoin on mo/mFs causing decresed phagocytosis, inhibition of oxidative burst, impaired secretion of IL-12 and decreased reponse to IFN? and b) a deficient TH1-cytokine response. 2. That the source of NTS bacteraemia is latent NTS infection of macrophages in the reticuloendothelial system (RES). Investigations: Immunological techniques will be used to assess TH1 activity and capacity, and mo/ mF function in SMA, and microbiological and molecular techniques will be used to look for a NTS carrier state.