Dual genetic absence of STAT6 and IL-10 does not abrogate anti-hyperglycemic effects of Schistosoma mansoni in streptozotocin-treated diabetic mice.

Schistosoma mansoni (Sm) is known to exert protective effects against various allergic and autoimmune disorders. It has been reported that this parasite protects NOD mice from spontaneous type 1 diabetes (T1D) and ameliorates streptozotocin (STZ)-induced T1D in wild-type mice. Here, we tried to clarify the anti-diabetic mechanisms of Sm in the latter model. Sm infection partially prevented the degradation of pancreatic islets and hyperglycemia in multiple low-dose (MLD) STZ-treated mice. Neither Treg cell depletion nor genetic absences of IL-10 and/or STAT6 abrogated the anti-hyperglycemic effects of Sm. Among M2 macrophage markers, Arg-1 and Ym1, but not Retnla, remained up-regulated in the pancreatic lymph nodes and in the spleens of STAT6/IL-10 double deficient (DKO) mice. Collectively, it is suggested that Sm exerts anti-diabetic effects on this experimental T1D model via Treg/IL-4/IL-13/IL-10-independent mechanisms. Augmented expressions of Arg-1 and Ym1 in the lymphoid organs adjacent to pancreas may be relevant to the anti-diabetic effects of Sm.

Enhanced transmission of malaria parasites to mosquitoes in a murine model of type 2 diabetes.

BACKGROUND: More than half of the world's population is at risk of malaria and simultaneously, many malaria-endemic regions are facing dramatic increases in the prevalence of type 2 diabetes. Studies in murine malaria models have examined the impact of malaria infection on type 2 diabetes pathology, it remains unclear how this chronic metabolic disorder impacts the transmission of malaria. In this report, the ability type 2 diabetic rodents infected with malaria to transmit parasites to Anopheles stephensi mosquitoes is quantified. METHODS: The infection prevalence and intensity of An. stephensi mosquitoes that fed upon control or type 2 diabetic C57BL/6 db/db mice infected with either lethal Plasmodium berghei NK65 or non-lethal Plasmodium yoelii 17XNL murine malaria strains were determined. Daily parasitaemias were also recorded. RESULTS: A higher percentage of mosquitoes (87.5 vs 61.5 % for P. yoelii and 76.9 vs 50 % for P. berghei) became infected following blood feeding on Plasmodium-infected type 2 diabetic mice compared to mosquitoes that fed on infected control animals, despite no significant differences in circulating gametocyte levels. CONCLUSIONS: These results suggest that type 2 diabetic mice infected with malaria are more efficient at infecting mosquitoes, raising the question of whether a similar synergy exists in humans.

Secreted proteins from the helminth Fasciola hepatica inhibit the initiation of autoreactive T cell responses and prevent diabetes in the NOD mouse.

Infections with helminth parasites prevent/attenuate auto-inflammatory disease. Here we show that molecules secreted by a helminth parasite could prevent Type 1 Diabetes (T1D) in nonobese diabetic (NOD) mice. When delivered at 4 weeks of age (coincident with the initiation of autoimmunity), the excretory/secretory products of Fasciola hepatica (FhES) prevented the onset of T1D, with 84% of mice remaining normoglycaemic and insulitis-free at 30 weeks of age. Disease protection was associated with suppression of IFN-γ secretion from autoreactive T cells and a switch to the production of a regulatory isotype (from IgG2a to IgG1) of autoantibody. Following FhES injection, peritoneal macrophages converted to a regulatory M2 phenotype, characterised by increased expression levels of Ym1, Arg-1, TGFß and PD-L1. Expression of these M2 genetic markers increased in the pancreatic lymph nodes and the pancreas of FhES-treated mice. In vitro, FhES-stimulated M2 macrophages induced the differentiation of Tregs from splenocytes isolated from naïve NOD mice. Collectively, our data shows that FhES contains immune-modulatory molecules that mediate protection from autoimmune diabetes via the induction and maintenance of a regulatory immune environment.

Type 2 diabetic and Alzheimer's disease mice present similar behavioral, cognitive, and vascular anomalies.

Type 2 diabetes (T2D) is considered a major risk factor for Alzheimer's disease (AD). To elucidate the links between both pathological conditions, we compared behavioral and cognitive functions, cerebral amyloid-ß peptide (Aß) levels and vasculature integrity of 11-month-old T2D and AD mice. For this purpose, we performed behavioral tests (open field, object recognition, Y-maze, and elevated plus maze tests), ELISA to assess plasma markers of endothelial/vascular dysfunction, spectrophotometric assays to evaluate cerebral vascular permeability and enzymatic activities, and immunohistochemistry for the assessment of Aß levels. Both T2D and AD showed similar behavioral and cognitive anomalies characterized by increased fear and anxiety and decreased learning and memory abilities. Interestingly, both groups of animals presented increased plasma markers of endothelial/vascular dysfunction and permeability of cerebral vasculature and impaired mitochondrial enzymatic activities. In addition, a significant increase in Aß levels was observed in the cortex and hippocampus of T2D mice. These results support the notion that T2D predisposes to cerebrovascular alterations, cognitive decline, and development of AD.

Parasitological and morphological study of Schistosoma mansoni and diabetes mellitus in mice.

Schistosomes are blood-dwelling flukes which are highly dependent on the host metabolism. The aim of this study was to investigate possible relationship between streptozotocin-induced diabetes and the outcome of acute murine schistosomiasis mansoni. Male and female SW mice were treated by a single intraperitoneally injected dose of streptozotocin (180 mg/kg). Seven days after induction, both control and diabetic animals were infected with 70 Schistosoma mansoni cercariae (BH strain). Diabetics and their controls were weighed 45 days after birth and for the last time prior to killing. Susceptibility to infection was evaluated twice a week by quantifying fecal egg excretion 7-9 weeks post-infection by the Kato-Katz' thick smear method. Mice were euthanized the day after the last fecal examination was performed. Adult worms were recovered from the portal system and mesenteric veins, whereas liver and intestine were removed for enumeration of egg load. No differences in worm length or in measurements of the reproductive organs, tegument, and suckers were detected. Also oviposition was unaffected as the total number of eggs per female worm from the liver, the small and the large intestine was the same in both groups. An oogram evaluation revealed a lower percentage of mature (23.0% vs. 40.7%) and a higher percentage of immature (69.1% vs. 51.7%) eggs in the small intestine of the diabetic mice. We suggest that principally a hampered egg passage through the intestine tissue caused this reduction and that probably both the eggs and the impaired host response play a role.

Microscopic investigations in a diabetic rat urinary bladder infected with Trichosomoides crassicauda.

Rats are widely used laboratory animals and have several parasites. One of these are helminths, known not only to cause serious effects on the experimental results in healthy subjects, but also in subjects with heavy infections. One of the relatively pathologic helminth is Trichosomoides crassicauda, which lives in the nodules of the urinary bladder. It is known that diabetics are more prone to infections with several microorganisms. Observations in a diabetic rat bladder showed T. crassicauda eggs inside the transitional epithelium, and structural changes in the bladder epithelium were evident. Urinary-bladder tissues taken from streptozotocin-injected diabetic subjects and citrate buffer-injected control subjects were fixed, embedded in araldite and investigated under a light microscope. Distinct changes in the histological structure of a diabetic urinary bladder transitional epithelium were observed after T. crassicauda infection. Many papillomas were formed and the epithelial tissues were completely degenerated. In addition, electron microscopic examinations also revealed degeneration of the subepithelial tissues.

Lower faecal egg excretion in chemically-induced diabetic mice infected with Schistosoma mansoni due to impaired egg maturation.

The effect of streptozotocin-induced diabetes mellitus was studied in mice infected with Schistosoma mansoni. Faecal egg excretion was lower in diabetic mice but worm load and total amount of eggs in the intestine tissue were equal to the control group. Evaluation of an oogram showed a great number of immature dead eggs and a low number of mature eggs in diabetic mice. It was therefore concluded that faecal egg excretion was lower in diabetic mice due to impaired egg maturation.

Trypanosoma brucei: infection in murine diabetes.

The course of infection due to Trypanosoma brucei infection was observed in genetically diabetic and streptozotocin-induced diabetic mice. A strain of T. brucei, TREU 667, was used which produces a chronic infection in C57BL/6(B6) mice lasting greater than 60 days. Genetic diabetic mice (+db/+db) are obese, and have elevated blood glucose levels, normal levels of insulin, and impaired cell-mediated immunity. Their littermates (m+/m+, m+/+db) are of normal weight, and are normoglycemic and immunocompetent. The infected +db/+db mice lived significantly longer than the nondiabetic littermates. In contrast to this finding, streptozotocin-induced diabetic B6 mice developed higher parasitemia and had shorter survival times than control B6 mice. Continuous treatment with insulin of these streptozotocin-induced diabetic mice led to normalization of blood glucose and a significant reduction of parasitemia. While hyperglycemia may be associated with higher parasitemia and death in streptozotozin-induced diabetes, genetic factors may play an additional role in the genetic models.

Host-parasite relationship in schistosomiasis mansoni in the mutation diabetic mouse (db/db).

Impairment of cell-mediated immunity has been described in chemically-induced as well as mutation diabetes in the mouse. The present report examines the host-parasite relationship during the acute phase of schistosomiasis mansoni in the mutation diabetic mouse (db/db). Cercarial penetration and maturation and egg output by adult worms were similar in the db/db mice and their littermate controls (db/+). In contrast, the pathological consequences of schistosomiasis were much less in the db/db mice. The mean liver weight computed as a percentage of body weight in db/db mice was 4.6 +/- 0.2 and following 8 weeks of infection it was 5.7 +/- 0.3 (difference is not statistically significant), whereas in infected db/+ mice it was 7.2 +/- 0.5. Infection in db/+ mice increased their mean portal pressure by 124% in contrast to an increase of only 12% in db/db animals. The most striking difference was noted in the mean granuloma diameter in the liver: 402 +/- 35 micrometer in db/+ in comparison to 147 +/- 10 micrometer in db/db mice (P less than 0.001). This study demonstrates the crucial role of the host granulomatous response in the causation of disease due to Schistosoma mansoni. Furthermore, it underlines the decreased pathological consequences when the host granulomatous response is suppressed, which can be compared to the response of modulated animals with chronic schistosomiasis.