Malaria-Associated L-Arginine Deficiency Induces Mast Cell-Associated Disruption to Intestinal Barrier Defenses against Nontyphoidal

Coinfection with malaria and nontyphoidal Salmonella serotypes (NTS) can cause life-threatening bacteremia in humans. Coin-fection with malaria is a recognized risk factor for invasive NTS, suggesting that malaria impairs intestinal barrier function. Here, we investigated mechanisms and strategies for prevention of coinfection pathology in a mouse model. Our findings reveal that malarial-parasite-infected mice, like humans, develop L-arginine deficiency, which is associated with intestinal mastocyto-sis, elevated levels of histamine, and enhanced intestinal permeability. Prevention or reversal of L-arginine deficiency blunts mastocytosis in ileal villi as well as bacterial translocation, measured as numbers of mesenteric lymph node CFU of noninvasive Escherichia coliNissle and Salmonella enterica serotype Typhimurium, the latter of which is naturally invasive in mice. Dietary supplementation of malarial-parasite-infected mice with L-arginine or L-citrulline reduced levels of ileal transcripts encoding interleukin-4 (IL-4), a key mediator of intestinal mastocytosis andmacromolecular permeability. Supplementation with L-citrul-line also enhanced epithelial adherens and tight junctions in the ilea of coinfected mice. These data suggest that increasing L-arginine bioavailability via oral supplementation can ameliorate malaria-induced intestinal pathology, providing a basis for test-ing nutritional interventions to reduce malaria-associated mortality in humans. Half of the global population is at risk for malaria, which resultsin nearly 1 million deaths annually, 86 % of which are of chil-dren (1). The majority of cases are in sub-Saharan Africa, where there is a high prevalence of coinfection with nontyphoidal Sal