Differing Burden and Epidemiology of Non-Typhi Salmonella Bacteremia in Rural and Urban Kenya, 2006–2009

Tabu, Collins; Breiman, Robert F.; Ochieng, Ben; Aura, Barrack; Cosmas, Leonard; Audi, Allan; Olack, Beatrice; Bigogo, Godfrey; Ongus, Juliette R.; Fields, Patricia I.; Mintz, Eric D.; Burton, Deron C.; Oundo, Joe; Feikin, Daniel R.

doi:10.1371/journal.pone.0031237

Cited by 78 publications

(101 citation statements)

References 40 publications

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“…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.…”

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confidence: 99%

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

et al. 2013

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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...

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mentioning

confidence: 99%

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

et al. 2013

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“…In addition, 50% of individuals with uncomplicated malaria have GI disturbances (24). Several features of malaria pathology suggest that the increased risk of developing bacteremia during malaria parasite and nontyphoidal Salmonella serotype (NTS) coinfection results from malaria-induced damage to the intestinal epithelium (25)(26)(27). Chau and colleagues demonstrate that malaria-associated hypoargininemia causes increased circulating and tissue histamine levels, mast cell activation, and ileal mastocytosis, which collectively alter intestinal epithelial integrity, predisposing the host to secondary bacterial infections (4).…”

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confidence: 99%

Arginine Cools the Inflamed Gut

Fritz

2013

Infect Immun

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Maintenance of immunophysiological homeostasis and regulation of gut barrier function are essential for the defense of the host. Severe alterations, including infections and chronic inflammation, have been associated with increased intestinal permeability, leading to deregulation of gut function and homeostasis. To establish and reinforce this crucial balance, the intestinal metabolism plays a key role and has to be tightly regulated since in the human intestinal mucosa, the protein fractional synthesis rate is approximately 50% per day. This value is higher than that of other major metabolically active tissues, such as liver and muscle, and depends on the accessibility of the metabolic precursor pool (1). The amino acid L-arginine (L-Arg) is a central intestinal metabolite, both as a constituent of protein synthesis and as a regulatory molecule limiting intestinal alterations and maintaining immunophysiological functions (1, 2). Infection-associated L-Arg deficiency has been shown to contribute to immunopathology, and clinical trials involving L-Arg administration have shown substantial decreases in inflammation and infectious complications (3). In this issue, Chau and colleagues demonstrate that malariaassociated hypoargininemia impairs intestinal barrier function and predisposes the host to coinfection with Salmonella. Increasing bioavailability of L-Arg through oral supplementation ameliorates intestinal inflammation and pathology, demonstrating that pharmacological intervention at the metabolic-precursor level can be utilized to regulate mucosal immunohomeostasis (4). METABOLISM AND CATABOLISM OF L-ARGININEL-Arg is derived from the diet, turnover of proteins, and endogenous production through synthesis from L-citrulline (L-Cit) and successive actions of argininosuccinate synthetase (AS) and argininosuccinate lyase (AL), the third and fourth enzymes of the urea cycle. The major site of L-Arg metabolism is the liver, where L-Arg generated in the urea cycle is rapidly converted to urea and ornithine by arginases, however, with no net synthesis of L-Arg. Although synthesis of L-Arg from L-Cit can occur in many cell types, a major part of endogenous synthesis occurs via "the intestinal-renal axis," a postnatally established collaboration between epithelial cells of the small intestine and proximal tubule cells of the kidney. In adult animals, L-Cit is produced primarily by intestinal epithelial cells from NH 3 , CO 2 , and ornithine by carbamylphosphate synthetase I and ornithine transcarbamylase, the first two enzymes of the urea cycle, and is supplied to the kidney and probably to other tissues for synthesis of L-Arg (2,5,6).L-Arg is a crucial amino acid that serves to modulate immune responses through conversion by several intracellular classes of enzymes, with isoforms of arginase and nitric oxide synthase (NOS) being the two major enzyme families exerting key immunological functions (7). However, catabolism of extracellular LArg requires active and regulated uptake via specific cationic amino acid transport...

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“…Furthermore, the inclusion of rural populations, which are usually more exposed to microorganisms than those in urban areas, is one of the causes for the increased rate of bacteremias in some studies. 23 For instance, in previous studies conducted in two urban areas of Gabon, bacteremias accounted for less than 5% of fevers. 4,21 In this study, the rate of bacteremias was higher and most were found in rural areas.…”

Section: Discussionmentioning

confidence: 94%

“…4,21 In rural areas of Gabon, bacteremias were under assessed, whereas studies conducted in other sub-Saharan African countries reported that the spectrum of bacteremias is more significant in rural areas. [13][14][15][16][17]20,22,23 To improve management of febrile illnesses in sub-Saharan Africa, the causes of bacteremia in febrile children should be investigated, and control groups of afebrile children should be systematically included. Indeed, the lack of afebrile control subjects in most studies conducted in sub-Saharan Africa on febrile patients is a major pitfall that compromises a solid understanding of the causes of fever in areas where asymptomatic carriage of microorganisms is common.…”

Section: Introductionmentioning

confidence: 99%

Co-circulation of Plasmodium and Bacterial DNAs in Blood of Febrile and Afebrile Children from Urban and Rural Areas in Gabon

Mourembou

Nzondo

Ndjoyi-Mbiguino

et al. 2016

The American Journal of Tropical Medicine and Hygiene

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Abstract. Malaria is considered to be the most common etiology of fever in sub-Saharan Africa while bacteremias exist but are under assessed. This study aimed to assess bacteremias and malaria in children from urban and rural areas in Gabon. DNA extracts from blood samples of 410 febrile and 60 afebrile children were analyzed using quantitative polymerase chain reaction. Plasmodium spp. was the microorganism most frequently detected in febrile (78.8%, 323/410) and afebrile (13.3%, 8/60) children, (P < 0.001). DNA from one or several bacteria were detected in 15 febrile patients (3.7%) but not in the controls (P = 0.1). This DNA was more frequently detected as co-infections among febrile children tested positive for Plasmodium (4.6%, 15/323) than in those tested negative for Plasmodium (0%, 0/87; P = 0.04). The bacteria detected were Streptococcus pneumoniae 2.4% (10/410), Staphylococcus aureus 1.7% (7/410), Salmonella spp. 0.7% (3/410), Streptococcus pyogenes 0.2% (1/410) and Tropheryma whipplei 0.2% (1/410) only in febrile children. Coxiella burnetii, Borrelia spp., Bartonella spp., Leptospira spp., and Mycobacterium tuberculosis were not observed. This paper reports the first detection of bacteremia related to T. whipplei in Gabon and shows that malaria decreases in urban areas but not in rural areas. Co-infections in febrile patients are common, highlighting the need to improve fever management strategies in Gabon.

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Differing Burden and Epidemiology of Non-Typhi Salmonella Bacteremia in Rural and Urban Kenya, 2006–2009

Cited by 78 publications

References 40 publications

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

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

Arginine Cools the Inflamed Gut

Co-circulation of Plasmodium and Bacterial DNAs in Blood of Febrile and Afebrile Children from Urban and Rural Areas in Gabon

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