Resistance of C57BL/6 Mice to Amoebiasis Is Mediated by Nonhemopoietic Cells but Requires Hemopoietic IL-10 Production

Hamano, Shinjiro; Asgharpour, Amon; Stroup, Suzanne; Wynn, Thomas A.; Leiter, Edward H.; Houpt, Eric R.

doi:10.4049/jimmunol.177.2.1208

Cited by 61 publications

(65 citation statements)

References 36 publications

(40 reference statements)

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“…Histological scoring for mucosal destruction/ulceration was performed in a blinded fashion as previously published (36,37): no mucosal damage was scored as 0, mild surface mucosal erosion scored as 1, focal ulceration or disrupted architecture scored as 2, and extensive mucosal damage and extension into deeper structures of the bowel wall as 3.…”

Section: Parasites and Intracecal Inoculation Trophozoites For Intramentioning

confidence: 99%

A mutation in the leptin receptor is associated with Entamoeba histolytica infection in children

et al. 2011

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Malnutrition substantially increases susceptibility to Entamoeba histolytica in children. Leptin is a hormone produced by adipocytes that inhibits food intake, influences the immune system, and is suppressed in malnourished children. Therefore we hypothesized that diminished leptin function may increase susceptibility to E. histolytica infection. We prospectively observed a cohort of children, beginning at preschool age, for infection by the parasite E. histolytica every other day over 9 years and evaluated them for genetic variants in leptin (LEP) and the leptin receptor (LEPR). We found increased susceptibility to intestinal infection by this parasite associated with an amino acid substitution in the cytokine receptor homology domain 1 of LEPR. Children carrying the allele for arginine (223R) were nearly 4 times more likely to have an infection compared with those homozygous for the ancestral glutamine allele (223Q). An association of this allele with amebic liver abscess was also determined in an independent cohort of adult patients. In addition, mice carrying at least 1 copy of the R allele of Lepr were more susceptible to infection and exhibited greater levels of mucosal destruction and intestinal epithelial apoptosis after amebic infection. These findings suggest that leptin signaling is important in mucosal defense against amebiasis and that polymorphisms in the leptin receptor explain differences in susceptibility of children in the Bangladesh cohort to amebiasis.

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Section: Parasites and Intracecal Inoculation Trophozoites For Intramentioning

confidence: 99%

A mutation in the leptin receptor is associated with Entamoeba histolytica infection in children

et al. 2011

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“…Five-week-old male CBA/J mice (Jackson Laboratories), which are susceptible to E. histolytica infection (17), were housed in a specificpathogen-free facility in microisolator cages and provided autoclaved food (lab diet 5010) and water ad libitum. Specific-pathogen-free status was monitored quarterly.…”

Section: Methodsmentioning

confidence: 99%

Role of Serum Amyloid A, Granulocyte-Macrophage Colony-Stimulating Factor, and Bone Marrow Granulocyte-Monocyte Precursor Expansion in Segmented Filamentous Bacterium-Mediated Protection from Entamoeba histolytica

et al. 2016

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Intestinal segmented filamentous bacteria (SFB) protect from ameba infection, and protection is transferable with bone marrow dendritic cells (BMDCs). SFB cause an increase in serum amyloid A (SAA), suggesting that SAA might mediate SFB's effects on BMDCs. Here we further explored the role of bone marrow in SFB-mediated protection. Transient gut colonization with SFB or SAA administration alone transiently increased the H3K27 histone demethylase Jmjd3, persistently increased bone marrow Csf2ra expression and granulocyte monocyte precursors (GMPs), and protected from ameba infection. Pharmacologic inhibition of Jmjd3 H3K27 demethylase activity during SAA treatment or blockade of granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling in SFB-colonized mice prevented GMP expansion, decreased gut neutrophils, and blocked protection from ameba infection. These results indicate that alteration of the microbiota and systemic exposure to SAA can influence myelopoiesis and susceptibility to amebiasis via epigenetic mechanisms. Gut microbiota-marrow communication is a previously unrecognized mechanism of innate protection from infection. Several studies have suggested that intestinal infection with one organism may persistently alter innate immune populations to provide protection from infection with unrelated pathogens (1-3). This idea has been referred to as innate trained immunity (4). However, the mechanism of how unrelated organisms might generate this protective yet nonspecific memory is not currently well described. Some studies have suggested that epigenetic modification of inflammatory genes in innate immune cells might underlie this effect (5, 6). Recent studies have also suggested that the microbiome might have long-term epigenetic effects on the immune system (7). Indeed, microbiota-produced serum soluble mediators and pathogen-associated molecular patterns (PAMPs) can impact myelopoiesis and hematopoiesis (8-10). We hypothesize that host-derived factors such as damage-associated molecular patterns (DAMPs) that are systemically induced by the microbiota may also have a role in altering hematopoiesis and susceptibility to infection.We have previously demonstrated that alteration of the microbiota via introduction of segmented filamentous bacteria (SFB) (50) can alter bone marrow-derived cells and protect from infection with the protozoan parasite Entamoeba histolytica (11). This protection was associated with increased gut neutrophils following amebic infection. This suggested that alteration of the microbiota might have a persistent influence on the bone marrow and myelopoiesis. To address this possibility further, we explored changes in bone marrow hematopoiesis during introduction of SFB to the gut microbiota. Serum amyloid A (SAA), a DAMP, was upregulated during SFB colonization (11,12) and is known to induce Jmjd3 (13), an epigenetic mediator and H3K27 demethylase linked to inflammation (14). SAA induced by the microbiota has also been shown to be important in neutrophil infiltration in a nonma...

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“…The cecum was removed 15 days postinfection, fixed in Bouin's solution (Sigma, St. Louis, MO), paraffin embedded, and stained with hematoxylin and eosin (H&E). Histopathology was scored in blinded fashion for inflammation score (0 to 5) and ameba score (0 to 5) as previously described (16). Briefly, the numbers of histologically visible amebas were scored (0, none; 1, present but difficult to locate; 2, occasional, up to 10% of the lumen occupied by ameba; 3, moderate, up to 25% of lumen occupied; 4, heavy, up to 50% of lumen occupied; and 5, virtually complete occupation of the lumen by ameba) and degree of inflammation was scored 0 to 5 (0, normal; 1, mucosal hyperplasia; 2, spotty infiltration of inflammatory cells not involving the entire thickness of the mucosa; 3, marked increase in inflammatory cells involving full thickness of mucosa; 4, marked increase in inflammatory cells of mucosa and submucosa, with tissue architecture intact; and 5, complete destruction of cecal architecture by inflammation).…”

Section: Methodsmentioning

confidence: 99%

Entamoeba histolytica Infection and Secreted Proteins Proteolytically Damage Enteric Neurons

et al. 2010

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The enteric protozoan parasite Entamoeba histolytica causes amebic colitis through disruption of the mucus layer, followed by binding to and destruction of epithelial cells. However, it is not known whether ameba infections or ameba components can directly affect the enteric nervous system. Analysis of mucosal innervations in the mouse model of cecal amebiasis showed that axon density was diminished to less than 25% of control. To determine whether amebas directly contributed to axon loss, we tested the effect of either E. histolytica secreted products (Eh-SEC) or soluble components (Eh-SOL) to an established coculture model of myenteric neurons, glia, and smooth muscle cells. Neuronal survival and axonal degeneration were measured after 48 h of exposure to graded doses of Eh-SEC or Eh-SOL (10 to 80 g/ml). The addition of 80 g of either component/ml decreased the neuron number by 30%, whereas the axon number was decreased by 50%. Cytotoxicity was specific to the neuronal population, since the glial and smooth muscle cell number remained similar to that of the control, and was completely abrogated by prior heat denaturation. Neuronal damage was partially prevented by the cysteine protease inhibitor E-64, showing that a heat-labile protease was involved. E. histolytica lysates derived from amebas deficient in the major secreted protease EhCP5 caused a neurotoxicity similar to that of wild-type amebas. We conclude that E. histolytica infection and ameba protease activity can cause selective damage to enteric neurons.Entamoeba histolytica is a protozoan enteric parasite of humans that colonizes the colon, where it typically causes asymptomatic luminal infections. However, in ca. 10% of individuals, the parasite invades the mucosa to cause amoebic colitis, characterized by ulcerative lesions, diarrhea, and fever and, in severe cases can disseminate to soft organs (39). Although normally seldom fatal, the consequences of ameba infection become significant in the immunosuppressed. The mechanism of infection in the intestine is complex and involves dissolution of the mucus layer by motile trophozoites, followed by adhesion and lysis of epithelial cells and invading leukocytes (8,9).Cysteine proteases are important in the differentiation and pathogenicity of E. histolytica, and its genome contains about 50 genes coding for cysteine peptidases (36). A number of in vivo and in vitro studies have implicated cysteine protease activity as a major mechanism of cell death of infected cells, as well as degradation of the extracellular matrix and activation of the complement system (31). Although cell-cell contact is thought to be required for intestinal invasion by E. histolytica trophozoites, amebic proteins have been shown to cause cellular responses in vitro. For example, E. histolytica trophozoitesecreted products caused mucin degradation by proteolytic degradation of cysteine domains (28). In addition, incubation of secreted products and soluble proteins with cultured intestinal epithelial cells resulted in the upregulation...

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Resistance of C57BL/6 Mice to Amoebiasis Is Mediated by Nonhemopoietic Cells but Requires Hemopoietic IL-10 Production

Cited by 61 publications

References 36 publications

A mutation in the leptin receptor is associated with Entamoeba histolytica infection in children

A mutation in the leptin receptor is associated with Entamoeba histolytica infection in children

Role of Serum Amyloid A, Granulocyte-Macrophage Colony-Stimulating Factor, and Bone Marrow Granulocyte-Monocyte Precursor Expansion in Segmented Filamentous Bacterium-Mediated Protection from Entamoeba histolytica

Entamoeba histolytica Infection and Secreted Proteins Proteolytically Damage Enteric Neurons

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