Malaria-Associatedl-Arginine Deficiency Induces Mast Cell-Associated Disruption to Intestinal Barrier Defenses against Nontyphoidal Salmonella Bacteremia

Abstract

bCoinfection with malaria and nontyphoidal Salmonella serotypes (NTS) can cause life-threatening bacteremia in humans. Coinfection 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 mastocytosis, 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 coli Nissle 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 and macromolecular permeability. Supplementation with L-citrulline also enhanced epithelial adherens and tight junctions in the ilea of coinfected mice. These data suggest that increasing Larginine bioavailability via oral supplementation can ameliorate malaria-induced intestinal pathology, providing a basis for testing nutritional interventions to reduce malaria-associated mortality in humans. Half of the global population is at risk for malaria, which results in nearly 1 million deaths annually, 86% of which are of children (1). The majority of cases are in sub-Saharan Africa, where there is a high prevalence of coinfection with nontyphoidal Salmonella serotypes (NTS) during the rainy season (2-5). While infections with NTS are normally self-limiting in immunocompetent children, coinfection with malaria can predispose to the development of deadly NTS bacteremia (6-9). During malaria infection, sequestration of parasitized red blood cells (RBCs) and capillary blockage are prominent in intestinal villi (10) and are associated with ischemia, malabsorption, and increased gastrointestinal (GI) permeability (11,12). These phenomena are not restricted to severe malaria; up to 50% of Nigerian children with uncomplicated malaria have GI disturbances (13). The mechanisms that underlie malaria-associated GI pathology and enhance the risk of bacteremia are incompletely understood (14), although recent data indicate that malaria-induced heme oxygenase-1 (HO-1) contributes to impaired resistance to NTS by reducing the production of reactive oxygen species (15). Beyond these findings, knowledge is limited and therapeutic options for coinfection are few in the face of high antibiotic resistance in areas of malaria endemicity (16). To support the development of novel therapeutic interventions for invasive bacterial disease, we developed a murine model of coinfection with Plasmodium yoelii and the NTS strain Salmonella enterica serotype Typhimurium ATCC 14028. In this...

Mast cells and histamine alter intestinal permeability during malaria parasite infection

“…Typhimurium alone (Roux et al, 2010). Further, we observed that rising parasitemia is associated with increased intestinal permeability, increased circulating and ileal histamine levels, and ileal mastocytosis, suggesting that allergic inflammation contributes to GI pathology in our mouse co-infection model (Chau et al, 2013). …”

Supplementation with Abscisic Acid Reduces Malaria Disease Severity and Parasite Transmission

“…decreased transcript levels of nitric oxide synthase (NOS) and increased transcript levels of the anti-inflammatory regulator peroxisome proliferator activated receptor gamma (PPARγ), which are regulated by ABA, in both the liver and spleen (Figure 3). 11,12,30,31 ABA supplementation of mice reduced P. yoelii transmission to mosquitoes. The effect of ABA on gametocytemia led us to investigate the effect of ABA supplementation on transmission of parasites from mice to mosquitoes.…”

“…Real-time polymerase chain reaction was performed using TaqMan ® Gene Expression Assays for mouse NOS2, PPARγ, and β-actin (Applied Biosystems) with volumes and cycling conditions as previously described. 30 Samples were analyzed in triplicate with 250 ng of cDNA per reaction to confirm uniformity of amplification. Data were normalized to β-actin and control messenger RNA (mRNA) levels.…”

Re-thinking the functions of IgA+plasma cells

“…113 Infection-associated L-Arg deficiency has been shown to contribute to immunopathology and predisposes to co-infections, 119 and clinical trials involving L-Arg administration have shown substantial decreases in inflammation and infectious complications.…”