Mast Cell-Mediated Changes in Smooth Muscle Contractility during Mouse Giardiasis

Li, Erqiu; Zhao, Aiping; Shea‐Donohue, Terez; Singer, Steven M.

doi:10.1128/iai.00596-07

Cited by 64 publications

(49 citation statements)

References 36 publications

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“…Many studies have attempted to correlate symptoms of disease with differences in parasite genetics (29). Our prior work supports roles for differences among parasite strains but also demonstrates important roles for the immune response in contributing to disease symptoms (8,27,28). These new data suggest that differences in the intestinal microbiota can contribute to differences in immune responses and may therefore also contribute to differences in clinical outcomes.…”

Section: Infection With G Duodenalis Results In Increased Cd4mentioning

confidence: 76%

“…The importance of the intestinal microbiota in gut homeostasis and immunity has been emphasized in recent years (24)(25)(26). In the adult mouse model of G. duodenalis infection, mice do not exhibit overt symptoms such as diarrhea or weight loss, but they do show reduced disaccharidase activity as well as increases in intestinal motility (8,27,28). In order to explore the role of the microbiota in G. duodenalis-induced immunity and immunopathology, we analyzed duodenal sucrase activity in C57BL/6 mice after a 7-day infection with and without antibiotic treatment.…”

Section: Resultsmentioning

confidence: 99%

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The Microbiota Contributes to CD8⁺T Cell Activation and Nutrient Malabsorption following Intestinal Infection with Giardia duodenalis

Keselman

Maloney

et al. 2016

Infect Immun

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Giardia duodenalis is a noninvasive luminal pathogen that impairs digestive function in its host in part by reducing intestinal disaccharidase activity. This enzyme deficiency has been shown in mice to require CD8 ؉ T cells. We recently showed that both host immune responses and parasite strain affected disaccharidase levels during murine giardiasis. However, high doses of antibiotics were used to facilitate infections in that study, and we therefore decided to systematically examine the effects of antibiotic use on pathogenesis and immune responses in the mouse model of giardiasis. We found that antibiotic treatment did not overtly increase the parasite burden but significantly limited the disaccharidase deficiency observed in infected mice. Moreover, while infected mice had more activated CD8 ؉ ␣␤ T cells in the small intestinal lamina propria, this increase was absent in antibiotictreated mice. Infection also led to increased numbers of CD4 ؉ ␣␤ T cells in the lamina propria and activation of T cell receptor ␥␦-expressing intraepithelial lymphocytes (IEL), but these changes were not affected by antibiotics. Finally, we show that activated CD8؉ T cells express gamma interferon (IFN-␥) and granzymes but that granzymes are not required for sucrase deficiency. We conclude that CD8؉ T cells become activated in giardiasis through an antibiotic-sensitive process and contribute to reduced sucrase activity. These are the first data directly demonstrating activation of CD8؉ T cells and ␥␦ T cells during Giardia infections. These data also demonstrate that disruption of the intestinal microbiota by antibiotic treatment prevents pathological CD8 ؉ T cell activation in giardiasis.T he protozoan Giardia duodenalis is a major cause of parasitic diarrheal disease worldwide. Infection with G. duodenalis provides an interesting model for studying mucosal immunity, as some of the immunopathology observed in human patients and infected animals resembles that of common noninfectious intestinal disorders. The reduction of intestinal disaccharidase enzymes, for example, is a pathological hallmark of giardiasis and is also commonly observed in gastroenteritis, celiac disease, ulcerative colitis, and Crohn's disease patients (1-4). Therefore, there are likely overlapping mechanisms involved. The reduction of disaccharidase enzymes in giardiasis results from a shortening of the intestinal epithelial microvilli structures and reflects a general impairment of digestion and nutrient absorption (5-7). We have demonstrated that wild-type mice exhibit reduced disaccharidase activity following infection with G. duodenalis but that CD4Another study has demonstrated that the adoptive transfer of purified CD8 ϩ T cells, but not CD4 ϩ T cells, from Giardia muris-infected mice into athymic naive recipients is sufficient to recapitulate shortening of microvilli and intestinal disaccharidase reduction (7). Collectively, these data suggest that CD8 ϩ T cells are involved in the pathological reduction of intestinal disaccharidases following infection...

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Section: Infection With G Duodenalis Results In Increased Cd4mentioning

confidence: 76%

Section: Resultsmentioning

confidence: 99%

The Microbiota Contributes to CD8⁺T Cell Activation and Nutrient Malabsorption following Intestinal Infection with Giardia duodenalis

Keselman

Maloney

et al. 2016

Infect Immun

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“…Giardia infection was also shown to cause significant increases in serum levels of histamine and mast cell protease, indicating that mast cells are not only recruited but also activated to degranulate (21). Mast cells were further implicated in generating smooth muscle hypercontractility following Giardia infection through pharmacological inhibition of degranulation ex vivo (40). Finally, intestinal hypermotility was also shown to be an important mechanism for parasite elimination, although a direct role for mast cells in this motility response in vivo has not been shown (41,42).…”

Section: Discussionmentioning

confidence: 99%

Complement Activation by Giardia duodenalis Parasites through the Lectin Pathway Contributes to Mast Cell Responses and Parasite Control

Tako

Singer

2016

Infect Immun

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Infection with Giardia duodenalis is one of the most common causes of diarrheal disease in the world. While numerous studies have identified important contributions of adaptive immune responses to parasite control, much less work has examined innate immunity and its connections to the adaptive response during this infection. We explored the role of complement in immunity to Giardia using mice deficient in mannose-binding lectin (Mbl2) or complement factor 3a receptor (C3aR). Both strains exhibited delayed clearance of parasites and a reduced ability to recruit mast cells in the intestinal submucosa. C3aR-deficient mice had normal production of antiparasite IgA, but ex vivo T cell recall responses were impaired. These data suggest that complement is a key factor in the innate recognition of Giardia and that recruitment of mast cells and activation of T cell immunity through C3a are important for parasite control. Giardia duodenalis is one of the most common protozoan infections of humans as well as other mammals throughout the world and is a leading cause of diarrheal disease in these species (1-3). Symptomatic infections occur in ϳ20 to 80% of humans with positive stool samples and are characterized by nausea, vomiting, epigastric pains, and diarrhea (1, 2, 4, 5). These symptoms are associated with nutrient malabsorption and can lead to weight loss and malnutrition in children, exposing this vulnerable group to failure to thrive and developmental problems (6, 7). Disease resolves spontaneously in Ͼ85% of cases. In certain cases, in spite of a healthy and fully developed immune system, the acute phase of the disease develops into chronic disease. In these cases, symptoms of the disease will reappear for short and recurrent periods (3,4,8). The mechanisms explaining interactions between the host and the parasite leading to parasite clearance and disease pathogenesis are poorly understood.Studies of immune responses against Giardia have demonstrated important roles for both innate and adaptive immunity (7, 9). Antibody production following infection is robust, and IgA is very effective at eliminating parasites (9). Antibody-independent roles of T cells can also eliminate infections (10). Early studies indicated that Giardia trophozoites are susceptible to killing by factors in nonimmune human serum, milk, and intestinal fluid (11-13). Recently, killing by normal serum was demonstrated to involve the lectin pathway (14), consistent with the expression of N-acetylglucosamine (GlcNAc) on the surface of trophozoites (15,16). Studies of cells of the innate immune system indicate that macrophages, dendritic cells, mast cells, and intestinal epithelial cells are all involved. In vitro macrophages have been shown to be capable of ingesting Giardia, and we recently showed that macrophages accumulate in the lamina propria following infection (17, 18). Bone marrow-derived dendritic cells mature in response to Giardia extracts, but cytokine production in response to Toll-like receptor (TLR) agonists is modulated toward interle...

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“…In vitro interaction models for G. lamblia and intestinal cells are well established [7][8][9][10][11], as are rodent models [12][13][14] and this has increased the knowledge of the infection [15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Release of metabolic enzymes by Giardia in response to interaction with intestinal epithelial cells

Ringqvist

Palm

Skarin

et al. 2008

Molecular and Biochemical Parasitology

154

139

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Giardia lamblia, an important cause of diarrheal disease, resides in the small intestinal lumen in close apposition to epithelial cells. Since the disease mechanisms underlying giardiasis are poorly understood, elucidating the specific interactions of the parasite with the host epithelium is likely to provide clues to understanding the pathogenesis. Here we tested the hypothesis that contact of Giardia lamblia with intestinal epithelial cells might lead to release of specific proteins. Using established co-culture models, intestinal ligated loops and a proteomics approach, we identified three G. lamblia proteins (arginine deiminase, ornithine carbamoyl transferase and enolase), previously recognized as immunodominant antigens during acute giardiasis. Release was stimulated by cell-cell interactions, since only small amounts of arginine deiminase and enolase were detected in the medium after culturing of G. lamblia alone. The secreted G. lamblia proteins were localized to the cytoplasm and the inside of the plasma membrane of trophozoites. Furthermore, in vitro studies with recombinant arginine deiminase showed that the secreted Giardia proteins can disable host innate immune factors such as nitric oxide production. These results indicate that contact of Giardia with epithelial cells triggers metabolic enzyme release, which might facilitate effective colonization of the human small intestine. a b s t r a c tGiardia lamblia, an important cause of diarrheal disease, resides in the small intestinal lumen in close apposition to epithelial cells. Since the disease mechanisms underlying giardiasis are poorly understood, elucidating the specific interactions of the parasite with the host epithelium is likely to provide clues to understanding the pathogenesis. Here we tested the hypothesis that contact of Giardia lamblia with intestinal epithelial cells might lead to release of specific proteins. Using established co-culture models, intestinal ligated loops and a proteomics approach, we identified three G. lamblia proteins (arginine deiminase, ornithine carbamoyl transferase and enolase), previously recognized as immunodominant antigens during acute giardiasis. Release was stimulated by cell-cell interactions, since only small amounts of arginine deiminase and enolase were detected in the medium after culturing of G. lamblia alone. The secreted G. lamblia proteins were localized to the cytoplasm and the inside of the plasma membrane of trophozoites. Furthermore, in vitro studies with recombinant arginine deiminase showed that the secreted Giardia proteins can disable host innate immune factors such as nitric oxide production. These results indicate that contact of Giardia with epithelial cells triggers metabolic enzyme release, which might facilitate effective colonization of the human small intestine.

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Mast Cell-Mediated Changes in Smooth Muscle Contractility during Mouse Giardiasis

Cited by 64 publications

References 36 publications

The Microbiota Contributes to CD8⁺T Cell Activation and Nutrient Malabsorption following Intestinal Infection with Giardia duodenalis

The Microbiota Contributes to CD8⁺T Cell Activation and Nutrient Malabsorption following Intestinal Infection with Giardia duodenalis

Complement Activation by Giardia duodenalis Parasites through the Lectin Pathway Contributes to Mast Cell Responses and Parasite Control

Release of metabolic enzymes by Giardia in response to interaction with intestinal epithelial cells

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Mast Cell-Mediated Changes in Smooth Muscle Contractility during Mouse Giardiasis

Cited by 64 publications

References 36 publications

The Microbiota Contributes to CD8+T Cell Activation and Nutrient Malabsorption following Intestinal Infection with Giardia duodenalis

The Microbiota Contributes to CD8+T Cell Activation and Nutrient Malabsorption following Intestinal Infection with Giardia duodenalis

Complement Activation by Giardia duodenalis Parasites through the Lectin Pathway Contributes to Mast Cell Responses and Parasite Control

Release of metabolic enzymes by Giardia in response to interaction with intestinal epithelial cells

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The Microbiota Contributes to CD8⁺T Cell Activation and Nutrient Malabsorption following Intestinal Infection with Giardia duodenalis

The Microbiota Contributes to CD8⁺T Cell Activation and Nutrient Malabsorption following Intestinal Infection with Giardia duodenalis