The relationship between malarial anaemia, neutrophil function and susceptibility to invasive bacterial disease.

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It is well documented that children with a recent history of acute malaria infection are at increased risk of developing severe, life threatening bacterial infections and we have recently described a biological mechanism that explains this association. Malaria causes destruction of red blood cells (haemolysis), releasing haemoglobin into the blood stream. Haemoglobin is degraded to heme and the heme is detoxified by an enzyme, heme-ozygenase-1 (HO-1). We found that HO-1 causes abnormal differentiation and loss of function of a white blood cell population (neutrophils) that are essential for killing bacteria. Thus, the anaemia caused by malaria infection causes the neutrophil dysfunction which predisposes to severe bacterial infections. Severe bacterial infections are much more common in areas where malaria is endemic than in countries where malaria is absent, and as malaria has begun to be controlled, the incidence of severe bacterial disease has also fallen. However, most children who develop severe bacterial infections do not have the history of a very recent episode of acute malaria infection. This has led us to hypothesise that chronic, low grade malaria infections (which are often, erroneously, described as "asymptomatic" infections and which are known to contribute to chronic malarial anaemia) may also increase the risk of severe bacterial infection. In most malaria endemic settings, the major burden of malaria infection is due to these "asymptomatic" cases, which greatly outnumber those with classical malaria symptoms. "Asymptomatically" infected individuals may thus represent a large, hitherto unrecognized, population that is at high risk of developing severe bacterial infection due to persistent neutrophil dysfunction. Thus, the central hypothesis underpinning this study is that chronic "asymptomatic" malaria leads to persistent haemolysis and neutrophil dysfunction, resulting in a decreased ability to control secondary bacterial infections. In addition, we hypothesise that treatment of chronic "asymptomatic" malaria will restore neutrophil function. To test this hypothesis we will determine the extent to which chronic, low grade "asymptomatic" malaria infection affects neutrophil function and the ability to control bacterial infections. We will begin by exploring the association between severity and duration of malarial anaemia, neutrophil function and susceptibility to bacterial disease in a mouse model system and then determine the extent to which these findings are relevant in humans by carrying out a cross-sectional study of Gambian children with chronic, subclinical malaria infection and anaemia. Finally, we will carry out a small proof-of-principle study to determine whether treating children with anti-malarial drugs will restore neutrophil function. If so, this may provide the justification for future clinical trials to determine whether public health programmes to treat "asymptomatic" malaria would reduce the incidence of severe bacterial infections in malaria endemic populations.