Bacteremia associated with malaria is a significant cause of mortality among children in sub-Saharan Africa and is also prevalent in adults in some malarious regions. Bacteremic children and adults are difficult to identify and many have blood infections with isolates that are multi-antibiotic-resistant. The high occurrence of bacteremia suggests that malaria induces a ?leaky gut,? an intestinal barrier dysfunction that facilitates escape of bacteria from the gut lumen into the blood with resulting serious sequelae. Recent studies have documented allergic inflammation in malaria, but no studies to date have linked this phenomenon to increased intestinal permeability observed in both acute and resolving clinical malaria. Our published and preliminary studies suggest that malaria-induced innate signals, including early cytokine synthesis and basophil activation, lead to mast cell influx into the intestine. Here, activated mast cells damage the physical barrier and suppress host immune responses that limit spread of enteric bacteria that cross the damaged physical barrier. In these studies, we will use our established models to examine the contributions of early innate signals and basophils ? cells for which no function in malaria has been described ? in promoting mastocytosis and the leaky gut phenotype we have observed. We will also determine to what extent malaria-induced mast cell degradation of the physical and immunological barriers of the intestine is dependent on mast cell proteases and mast cell- derived cytokines that are relevant to our observations. It is our expectation that our work will elucidate new mechanisms underlying the importance of allergic inflammation to mucosal barrier degradation in malaria. The outcome of the proposed research is likely to provide novel paradigms for future interventions to reduce the incidence of malaria-associated bacteremia. This work is significant because it directly addresses an important co-morbidity of malaria and will provide novel mechanistic insights into well-documented ? and heretofore unlinked ? clinical observations.
More than 6% of African children with severe falciparum malaria (SFM) have bacteremia (intestinal bacteria in the blood) from a ?leaky gut? and these children have a case-fatality rate, in some reports, up to 10-fold higher than children with SFM alone. Bacteremia is also relatively frequent in adults (>13% in some settings) and, as in children, bacteremic adults are sicker than non-bacteremic adults, are difficult to identify, and difficult to treat because of high rates of antibiotic resistance. While there is a significant need to reduce the incidence of bacteremia, the underlying biology of this problem is unknown so we will use our established malaria model to identify mechanisms that could be targeted in future efforts aimed at mitigating these adverse impacts.
