Early Th2 response to Plasmodium yoelii infection is associated with intestinal mastocytosis, bacteremia and elevated intestinal permeability

Abstract The presence of bacteria in the blood or bacteremia is complication of malaria that occurs across a broad range of ages and clinical manifestations and is associated with increased morbidity and mortality, but the factors that predispose patients to developing this “leaky gut” phenotype are poorly understood. Enteric bacteria are thought to translocate from the intestinal lumen into circulation via damaged tight and adherens junctions. Mast cell (MC) activation in both humans and mice is known to disrupt epithelial junction integrity and increase intestinal permeability. Increases in intestinal MCs have been noted in both mouse and primate models of malaria. Activated MCs are potent sources of Th2 cytokines, histamine, and other factors that can influence both the innate and adaptive immune response. To better understand the temporal patterns of both the circulating and intestinal immune response to non-lethal infection, we infected C57BL/6J mice with Plasmodium yoelii yoelii 17XNL and analyzed circulating white blood cell counts, bacteria levels, cytokines, intestinal permeability to dextran and ileal MC numbers 1, 2, 4, 6, 8 and 10 days post infection. We observed an early elevation (day 4) in Th2 cytokines interleukin (IL)-4, IL-6 and IL-10. Interestingly, we also observed an early elevation in basophils and eosinophils, granulocytes associated with allergic inflammation. These findings coincided with the first appearance of MCs in the ileum and preceded the development of bacteremia (day 6) and elevations in intestinal permeability to dextran (day 8), suggesting the early Th2 response to infection is a potential driver of mastocytosis and increased permeability.