Match!

Cysteine Protease–Dependent Mucous Disruptions and Differential Mucin Gene Expression in Giardia duodenalis Infection

Published on Nov 1, 2017in American Journal of Pathology3.762
· DOI :10.1016/j.ajpath.2017.07.009
Christina B. Amat5
Estimated H-index: 5
(U of C: University of Calgary),
Jean-Paul Motta15
Estimated H-index: 15
(U of C: University of Calgary)
+ 2 AuthorsAndre G. Buret47
Estimated H-index: 47
(U of C: University of Calgary)
Abstract
The intestinal mucous layer provides a critical host defense against pathogen exposure and epithelial injury, yet little is known about how enteropathogens may circumvent this physiologic barrier. Giardia duodenalis is a small intestinal parasite responsible for diarrheal disease and chronic postinfectious illness. This study reveals a complex interaction at the surface of epithelial cells, between G. duodenalis and the intestinal mucous layer. Here, we reveal mechanisms whereby G. duodenalis evades and disrupts the first line of host defense by degrading human mucin-2 (MUC2), depleting mucin stores and inducing differential gene expression in the mouse small and large intestines. Human colonic biopsy specimens exposed to G. duodenalis were depleted of mucus, and in vivo mice infected with G. duodenalis had a thinner mucous layer and demonstrated differential Muc2 and Muc5ac mucin gene expression. Infection in Muc2 −/− mice elevated trophozoite colonization in the small intestine and impaired weight gain. In vitro , human LS174T goblet-like cells were depleted of mucus and had elevated levels of MUC2 mRNA expression after G. duodenalis exposure. Importantly, the cysteine protease inhibitor E64 prevented mucous degradation, mucin depletion, and the increase in MUC2 expression. This article describes a novel role for Giardia 's cysteine proteases in pathogenesis and how Giardia 's disruptions of the mucous barrier facilitate bacterial translocation that may contribute to the onset and propagation of disease.
  • References (59)
  • Citations (9)
📖 Papers frequently viewed together
51 Citations
20152.78PLOS ONE
6 Authors (Amol Bhargava, ..., Andre G. Buret)
25 Citations
34 Citations
78% of Scinapse members use related papers. After signing in, all features are FREE.
References59
Newest
#1Jennifer K. Beatty (U of C: University of Calgary)H-Index: 7
#2Sarah Akierman (U of C: University of Calgary)H-Index: 4
Last. Andre G. Buret (U of C: University of Calgary)H-Index: 47
view all 12 authors...
34 CitationsSource
#1V Morampudi (Family Research Institute)H-Index: 1
#2U Dalwadi (Family Research Institute)H-Index: 1
Last. Bruce A. Vallance (Family Research Institute)H-Index: 49
view all 12 authors...
Intestinal goblet cells are potentially key players in controlling susceptibility to ulcerative colitis (UC). Although impaired mucin (Muc2) production by goblet cells increases microbial stimulation of the colonic mucosa, goblet cells secrete other mediators that may influence or promote UC development. Correspondingly, Muc2-deficient (−/−) mice develop spontaneous colitis, concurrent with the dramatic upregulation of the goblet cell mediator, resistin-like molecule-beta (RELM-β). Testing RELM-...
28 CitationsSource
#1Andre G. Buret (U of C: University of Calgary)H-Index: 47
Recent observations indicate that acute enteric infections may contribute to various intestinal and extra-intestinal disorders long after elimination of the inciting microorganism. The mechanisms remain unclear. This review discusses how alterations to the gut microbiota by enteropathogens during the acute stage of an infection may at least in part contribute to these presentations. After providing a critical discussion of the biology of the human intestinal microbiota, the review presents recen...
3 CitationsSource
#1Marie C. M. Halliez (U of C: University of Calgary)H-Index: 4
#2Jean-Paul Motta (U of C: University of Calgary)H-Index: 15
Last. Andre G. Buret (U of C: University of Calgary)H-Index: 47
view all 12 authors...
Irritable bowel syndrome (IBS) is the most frequent functional gastrointestinal disorder. It is characterized by abdominal hypersensitivity, leading to discomfort and pain, as well as altered bowel habits. While it is common for IBS to develop following the resolution of infectious gastroenteritis [then termed postinfectious IBS (PI-IBS)], the mechanisms remain incompletely understood. Giardia duodenalis is a cosmopolitan water-borne enteropathogen that causes intestinal malabsorption, diarrhea,...
21 CitationsSource
#1Steve Cornick (U of C: University of Calgary)H-Index: 7
#3Kris Chadee (U of C: University of Calgary)H-Index: 31
Critical to the pathogenesis of intestinal amebiasis, Entamoeba histolytica (Eh) induces mucus hypersecretion and degrades the colonic mucus layer at the site of invasion. The parasite component(s) responsible for hypersecretion are poorly defined, as are regulators of mucin secretion within the host. In this study, we have identified the key virulence factor in live Eh that elicits the fast release of mucin by goblets cells as cysteine protease 5 (EhCP5) whereas, modest mucus secretion occurred...
19 CitationsSource
#1Eduardo R. Cobo (U of C: University of Calgary)H-Index: 17
#2Vanessa Kissoon-Singh (U of C: University of Calgary)H-Index: 7
Last. Kris Chadee (U of C: University of Calgary)H-Index: 31
view all 4 authors...
In this study we identified mechanisms at the colonic mucosa by which MUC2 mucin regulated the production of β-defensin in a proinflammatory milieu but functionally protected susceptible bacteria from its antimicrobial effects. The regulator role of MUC2 on production of β-defensin 2 in combination with the proinflammatory cytokine interleukin-1β (IL-1β) was confirmed using purified human colonic MUC2 mucin and colonic goblet cells short hairpin RNA (shRNA) silenced for MUC2. In vivo, Muc2−/− mi...
34 CitationsSource
#1Brendan R. E. Ansell (University of Melbourne)H-Index: 10
#2Malcolm J. McConville (University of Melbourne)H-Index: 61
Last. Aaron R. Jex (University of Melbourne)H-Index: 36
view all 7 authors...
Giardia duodenalis is a microaerophilic parasite of the human gastrointestinal tract and a major contributor to diarrheal and post-infectious chronic gastrointestinal disease world-wide. Treatment ...
46 CitationsSource
#1Amol Bhargava (U of C: University of Calgary)H-Index: 6
#2James A. Cotton (U of C: University of Calgary)H-Index: 8
Last. Andre G. Buret (U of C: University of Calgary)H-Index: 47
view all 6 authors...
25 CitationsSource
#1James A. Platts-Mills (UVA: University of Virginia)H-Index: 27
#2Sudhir Babji (Christian Medical College & Hospital)H-Index: 20
Last. Eric R. Houpt (UVA: University of Virginia)H-Index: 44
view all 36 authors...
Summary Background Most studies of the causes of diarrhoea in low-income and middle-income countries have looked at severe disease in people presenting for care, and there are few estimates of pathogen-specific diarrhoea burdens in the community. Methods We undertook a birth cohort study with not only intensive community surveillance for diarrhoea but also routine collection of non-diarrhoeal stools from eight sites in South America, Africa, and Asia. We enrolled children within 17 days of birth...
315 CitationsSource
#1Andre G. Buret (U of C: University of Calgary)H-Index: 47
#2Christina B. Amat (U of C: University of Calgary)H-Index: 5
Last. James A. Cotton (U of C: University of Calgary)H-Index: 8
view all 8 authors...
Giardia duodenalis is a very common, ubiquitous, intestinal protozoan parasite infecting animals and humans. Of the eight distinct genetic assemblages known to date, assemblages A and B are infectious to humans. Giardia is the most commonly recognized cause of traveller’s diarrhea. Giardiasis impairs weight gain and is responsible for a variety of extra-intestinal and post-infectious complications, including post-infectious irritable bowel syndrome, chronic fatigue, failure to thrive, and cognit...
17 CitationsSource
Cited By9
Newest
#1Anna Manko-Prykhoda (U of C: University of Calgary)
#2Thibault Allain (U of C: University of Calgary)H-Index: 5
Last. Paul L. Beck (U of C: University of Calgary)H-Index: 51
view all 11 authors...
Abstract Polymicrobial infections of the gastro-intestinal tract are common in areas with poor sanitation. Disease outcome is the result of complex interactions between the host and pathogens. Such interactions lie at the core of future management strategies of enteric diseases. In developed countries of the world, Giardia duodenalis is a common cause of diarrheal disease. In contrast, giardiasis appears to protect children against diarrhea in countries with poor sanitation, via obscure mechanis...
Source
#1Andre G. Buret (U of C: University of Calgary)H-Index: 47
Source
#1Thibault Allain (U of C: University of Calgary)H-Index: 5
#2Andre G. Buret (U of C: University of Calgary)H-Index: 47
Abstract Giardia is an important cause of diarrhoea, and results in post-infectious and extra-intestinal complications. This chapter presents a state-of-the art of our understanding of how this parasite may cause such abnormalities, which appear to develop at least in part in Assemblage-dependent manner. Findings from prospective longitudinal cohort studies indicate that Giardia is one of the four most prevalent enteropathogens in early life, and represents a risk factor for stunting at 2 years ...
Source
#1Feifei Xu (Dal: Dalhousie University)
#1Feifei Xu (Uppsala University)H-Index: 6
Last. Jon Jerlström-Hultqvist (Dal: Dalhousie University)H-Index: 1
view all 9 authors...
Diplomonad parasites of the genus Giardia have adapted to colonizing different hosts, most notably the intestinal tract of mammals. The human-pathogenic Giardia species, Giardia intestinalis, has been extensively studied at the genome and gene expression level, but no such information is available for other Giardia species. Comparative data would be particularly valuable for Giardia muris, which colonizes mice and is commonly used as a prototypic in vivo model for investigating host responses to...
Source
#1Thibault Allain (U of C: University of Calgary)H-Index: 5
#2Elena Fekete (U of C: University of Calgary)H-Index: 2
Last. Andre G. Buret (U of C: University of Calgary)H-Index: 47
view all 3 authors...
Giardia duodenalis is one of the most prevalent human enteropathogens and a major cause of diarrheal disease worldwide. Cysteine proteases (CPs) have been identified as major virulence factors in protozoan parasites, playing important roles in disease pathogenesis and in parasitic life cycles. G. duodenalis exhibits high proteolytic activity, and CPs play significant roles in giardiasis. Giardia CPs are directly involved in intestinal epithelial junctional complex disruption, intestinal epitheli...
2 CitationsSource
#1Jingyi Liu (Uppsala University)H-Index: 3
#2Staffan G. Svärd (Uppsala University)H-Index: 22
Last. Christian Klotz (RKI: Robert Koch Institute)H-Index: 9
view all 3 authors...
Source
#1Andre G. Buret (U of C: University of Calgary)H-Index: 47
#2Jean-Paul Motta (University of Toulouse)H-Index: 15
Last. John L. Wallace (U of C: University of Calgary)H-Index: 71
view all 5 authors...
Gut microbiota interacting with an intact mucosal surface are key to the maintenance of homeostasis and health. This review discusses the current state of knowledge of the biofilm mode of growth of these microbiota communities, and how in turn their disruptions may cause disease. Beyond alterations of relative microbial abundance and diversity, the aim of the review is to focus on the disruptions of the microbiota biofilm structure and function, the dispersion of commensal bacteria, and the mech...
7 CitationsSource
Abstract During the course of giardiasis in humans and experimental models, G. duodenalis trophozoites express and secrete several proteins (ESPs) affecting structural, cellular and soluble components of the host intestinal milieu. These include the toxin-like molecules CRP136 and ESP58 that induce intestinal hyper-peristalsis. After the completion of the Giardia genome database and using up-to date transcriptomic and proteomic approaches, secreted ‘virulence factors’ have also been identified a...
4 CitationsSource
#1Steven M. Singer (Georgetown University)H-Index: 22
#2Marc Y. Fink (Georgetown University)H-Index: 3
Last. Vanessa V. Angelova (Georgetown University)
view all 3 authors...
Abstract Infection with Giardia produces a wide range of clinical outcomes. Acutely infected patients may have no overt symptoms or suffer from severe cramps, diarrhea, nausea and even urticaria. Recently, post-infectious irritable bowel syndrome and chronic fatigue syndrome have been identified as long-term sequelae of giardiasis. Frequently, recurrent and chronic Giardia infection is considered a major contributor to stunting in children from low and middle income countries. Perhaps the most u...
Source
#1Jingyi Liu (Uppsala University)H-Index: 3
#2Zhirong Fu (Uppsala University)H-Index: 4
Last. Staffan G. Svärd (Uppsala University)H-Index: 22
view all 4 authors...
Giardia intestinalis is a protozoan parasite and the causative agent of giardiasis, a common diarrheal disease. Cysteine protease (CP) activities have been suggested to be involved in Giardia's pat ...
3 CitationsSource