Trichuris muris

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Kathryn J. Else - One of the best experts on this subject based on the ideXlab platform.

  • Trichuris muris infection drives cell intrinsic il4r alpha independent colonic relmα macrophages
    PLOS Pathogens, 2021
    Co-Authors: Ruth Forman, Larisa Logunova, Hannah Smith, Kelly Wemyss, Iris Mair, Louis Boon, Judith E Allen, Werner Muller, Joanne L Pennock, Kathryn J. Else
    Abstract:

    The intestinal nematode parasite Trichuris muris dwells in the caecum and proximal colon driving an acute resolving intestinal inflammation dominated by the presence of macrophages. Notably, these macrophages are characterised by their expression of RELMα during the resolution phase of the infection. The RELMα+ macrophage phenotype associates with the presence of alternatively activated macrophages and work in other model systems has demonstrated that the balance of classically and alternatively activated macrophages is critically important in enabling the resolution of inflammation. Moreover, in the context of type 2 immunity, RELMα+ alternatively activated macrophages are associated with the activation of macrophages via the IL4Rα. Despite a breadth of inflammatory pathologies associated with the large intestine, including those that accompany parasitic infection, it is not known how colonic macrophages are activated towards an alternatively activated phenotype. Here, we address this important knowledge gap by using Trichuris muris infection, in combination with transgenic mice (IL4Rαfl/fl.CX3CR1Cre) and IL4Rα-deficient/wild-type mixed bone marrow chimaeras. We make the unexpected finding that education of colonic macrophages towards a RELMα+, alternatively activated macrophage phenotype during T. muris infection does not require IL4Rα expression on macrophages. Further, this independence is maintained even when the mice are treated with an anti-IFNγ antibody during infection to create a strongly polarised Th2 environment. In contrast to RELMα, PD-L2 expression on macrophages post infection was dependent on IL4Rα signalling in the macrophages. These novel data sets are important, revealing a surprising cell-intrinsic IL4R alpha independence of the colonic RELMα+ alternatively activated macrophage during Trichuris muris infection.

  • morphological variability in the mucosal attachment site of Trichuris muris revealed by x ray microcomputed tomography
    International Journal for Parasitology, 2021
    Co-Authors: James Osullivan, Sheena M Cruickshank, P J Withers, Kathryn J. Else
    Abstract:

    Abstract Parasitic infections can be challenging to study because two dimensional light and electron microscopy are often limited in visualising complex and inaccessible attachment sites. Exemplifying this, Trichuris spp. inhabit a tunnel of epithelial cells within the host caecum and colon. A significant global burden of this infection persists, partly because available anthelminthics lack efficacy, although the mechanisms underlying this remain unknown. Consequently, there is a need to pioneer new approaches to better characterize the parasite niche within the host and investigate how variation in its morphology and integrity may contribute to resistance to therapeutic intervention. To address these aims, we exploited three-dimensional X-ray micro-computed tomography (microCT) to image the mouse whipworm, Trichuris muris, in caeca of wild-type C57BL/6 and SCID mice ex vivo. Using osmium tetroxide staining to effectively enhance the contrast of worms, we found that a subset exhibited preferential positioning towards the bases of the intestinal crypts. Moreover, in one rare event, we demonstrated whipworm traversal of the lamina propria. This morphological variability contradicts widely accepted conclusions from conventional microscopy of the parasite niche, showing Trichuris in close contact with the host proliferative and immune compartments that may facilitate immunomodulation. Furthermore, by using a skeletonization-based approach we demonstrate considerable variation in tunnel length and integrity. The qualitative and quantitative observations provide a new morphological point of reference for future in vitro study of host-Trichuris interactions, and highlight the potential of microCT to characterise enigmatic host-parasite interactions more accurately.

  • Trichuris muris as a tool for holistic discovery research from translational research to environmental bio tagging
    Parasitology, 2021
    Co-Authors: Iris Mair, Kathryn J. Else, Ruth Forman
    Abstract:

    Trichuris spp. (whipworms) are intestinal nematode parasites which cause chronic infections associated with significant morbidities. Trichuris muris in a mouse is the most well studied of the whipworms and research on this species has been approached from a number of different disciplines. Research on T. muris in a laboratory mouse has provided vital insights into the host–parasite interaction through analyses of the immune responses to infection, identifying factors underpinning host susceptibility and resistance. Laboratory studies have also informed strategies for disease control through anthelmintics and vaccine research. On the contrary, research on naturally occurring infections with Trichuris spp. allows the analysis of the host–parasite co-evolutionary relationships and parasite genetic diversity. Furthermore, ecological studies utilizing Trichuris have aided our knowledge of the intricate relationships amongst parasite, host and environment. More recently, studies in wild and semi-wild settings have combined the strengths of the model organism of the house mouse with the complexities of context-dependent physiological responses to infection. This review celebrates the extraordinarily broad range of beneficiaries of whipworm research, from immunologists and parasitologists, through epidemiologists, ecologists and evolutionary biologists to the veterinary and medical communities.

  • investigating the importance of b cells and antibodies during Trichuris muris infection using the igmi mouse
    Journal of Molecular Medicine, 2020
    Co-Authors: Rinal Sahputra, Ruth Forman, Iris Mair, Werner Muller, Emma A Murphy, Muhammad Z H Fadlullah, Ari Waisman, Kathryn J. Else
    Abstract:

    The IgMi mouse has normal B cell development; its B cells express an IgM B cell receptor but cannot class switch or secrete antibody. Thus, the IgMi mouse offers a model system by which to dissect out antibody-dependent and antibody-independent B cell function. Here, we provide the first detailed characterisation of the IgMi mouse post-Trichuris muris (T. muris) infection, describing expulsion phenotype, cytokine production, gut pathology and changes in T regulatory cells, T follicular helper cells and germinal centre B cells, in addition to RNA sequencing (RNA seq) analyses of wild-type littermates (WT) and mutant B cells prior to and post infection. IgMi mice were susceptible to a high-dose infection, with reduced Th2 cytokines and elevated B cell-derived IL-10 in mesenteric lymph nodes (MLN) compared to controls. A low-dose infection regime revealed IgMi mice to have significantly more apoptotic cells in the gut compared to WT mice, but no change in intestinal inflammation. IL-10 levels were again elevated. Collectively, this study showcases the potential of the IgMi mouse as a tool for understanding B cell biology and suggests that the B cell plays both antibody-dependent and antibody-independent roles post high- and low-dose T. muris infection.

  • Characterisation of cuticular inflation development and ultrastructure in Trichuris muris using correlative X-ray computed tomography and electron microscopy
    Scientific Reports, 2020
    Co-Authors: James D. B. O’sullivan, Sheena M Cruickshank, Tobias Starborg, Philip J. Withers, Kathryn J. Else
    Abstract:

    The parasitic nematode Trichuris trichiura is a significant burden on public health in developing countries, and currently available drugs exhibit a poor cure rate. Worms live within a specialised tunnel of host intestinal epithelial cells and have anterior-ventral projections of the cuticle termed “cuticular inflations”, which are thought to be involved in host-parasite interactions. This work aimed to characterise structure and suggest a function of cuticular inflations in the most tractable and widely-used model of trichuriasis, Trichuris muris . Using scanning electron microscopy, we show for the first time that most cuticular inflations develop between the second and third larval moults. Correlative X-ray computed tomography (CT)-steered Serial Block Face Scanning Electron Microscopy (SBF-SEM) and transmission electron microscopy enabled ultrastructural imaging of cuticular inflations, and showed the presence of an additional, web-like layer of cuticle between the median and cortical layers of the inflation. Additionally, we characterised variation in inflation morphology, resolving debate as to the inflations’ true shape in situ . Cells underlying the inflations had many mitochondria, and we highlight their potential capacity for active transport as an area for future investigation. Overall, insights from the powerful imaging techniques used provide an excellent basis for future study of cuticular inflation function.

Richard K Grencis - One of the best experts on this subject based on the ideXlab platform.

  • Trichuris muris and comorbidities within a mouse model context
    Parasitology, 2021
    Co-Authors: Kelly S Hayes, Richard K Grencis
    Abstract:

    Trichuris muris is a mouse intestinal parasitic nematode that inhabits the large intestine of its host and induces a strong immune response. The effects of this strong anti-parasite response can be found locally within the intestinal niche and also systemically, having effects on multiple organs. Additionally, the anti-parasite response can have multiple effects on infectious organisms and on microbiota that the host is harbouring. It has been shown that Th1 responses induced by T. muris can affect progression of bowel inflammation, cause colitic-like intestinal inflammation, reduce barrier function and intestinal mucosal responses. In the brain, T. muris can exacerbate stroke outcome and other neurological conditions. In the lung, T. muris can suppress airway inflammation and alter immune responses to other parasites. Additionally, T. muris induced responses can inhibit anti-tumour immunity. Although this parasite maintains a localized niche in the large intestine, its effects can be far-reaching and substantially impact other infections through modulation of bystander immune responses.

  • development of caecaloids to study host pathogen interactions new insights into immunoregulatory functions of Trichuris muris extracellular vesicles in the caecum
    International Journal for Parasitology, 2020
    Co-Authors: Maria A Duquecorrea, Richard K Grencis, Fernanda Schreiber, Faye H Rodgers, David Goulding, Sally Forrest, Ruby White, Amy H Buck, Matthew Berriman
    Abstract:

    The caecum, an intestinal appendage in the junction of the small and large intestines, displays a unique epithelium that serves as an exclusive niche for a range of pathogens including whipworms (Trichuris spp.). While protocols to grow organoids from small intestine (enteroids) and colon (colonoids) exist, the conditions to culture organoids from the caecum have yet to be described. Here, we report methods to grow, differentiate and characterise mouse adult stem cell-derived caecal organoids, termed caecaloids. We compare the cellular composition of caecaloids with that of enteroids, identifying differences in intestinal epithelial cell populations that mimic those found in the caecum and small intestine. The remarkable similarity in the intestinal epithelial cell composition and spatial conformation of caecaloids and their tissue of origin enables their use as an in vitro model to study host interactions with important caecal pathogens. Thus, exploiting this system, we investigated the responses of caecal intestinal epithelial cells to extracellular vesicles secreted/excreted by the intracellular helminth Trichuris muris. Our findings reveal novel immunoregulatory effects of whipworm extracellular vesicles on the caecal epithelium, including the downregulation of responses to nucleic acid recognition and type-I interferon signalling.

  • development of caecaloids to study host pathogen interactions new insights into immunoregulatory functions of Trichuris muris extracellular vesicles in the caecum
    bioRxiv, 2020
    Co-Authors: Maria A Duquecorrea, Richard K Grencis, Fernanda Schreiber, Faye H Rodgers, David Goulding, Sally Forrest, Ruby White, Amy H Buck, Matthew Berriman
    Abstract:

    The caecum, an intestinal appendage in the junction of the small and large intestines, displays a unique epithelium that serves as an exclusive niche for a range of pathogens including whipworms (Trichuris spp). While protocols to grow organoids from small intestine (enteroids) and colon (colonoids) exist, the conditions to culture organoids from the caecum have yet to be described. Here, we report methods to grow, differentiate and characterise mouse adult stem cell-derived caecal organoids, termed caecaloids. We compare the cellular composition of caecaloids to that of enteroids identifying differences in intestinal epithelial cell (IEC) populations that mimic those found in the caecum and small intestine. The remarkable similarity in the IECs composition and spatial conformation of caecaloids and their tissue of origin enables their use as an in vitro model to study host interactions with important caecal pathogens. Thus, exploiting this system we investigated the responses of caecal IECs to extracellular vesicles (EVs) secreted/excreted by the intracellular helminth Trichuris muris. Our findings reveal novel immunoregulatory effects of whipworm EVs on the caecal epithelium, including the downregulation of responses to nucleic acid recognition and type-I interferon (IFN) signalling.

  • trickle infection and immunity to Trichuris muris
    PLOS Pathogens, 2019
    Co-Authors: Maya Glover, David J Thornton, Stefano A P Colombo, Richard K Grencis
    Abstract:

    The majority of experiments investigating the immune response to gastrointestinal helminth infection use a single bolus infection. However, in situ individuals are repeatedly infected with low doses. Therefore, to model natural infection, mice were repeatedly infected (trickle infection) with low doses of Trichuris muris. Trickle infection resulted in the slow acquisition of immunity reflected by a gradual increase in worm burden followed by partial expulsion. Flow cytometry revealed that the CD4+ T cell response shifted from Th1 dominated to Th2 dominated, which coincided with an increase in Type 2 cytokines. The development of resistance following trickle infection was associated with increased worm expulsion effector mechanisms including goblet cell hyperplasia, Muc5ac production and increased epithelial cell turn over. Depletion of CD4+ T cells reversed resistance confirming their importance in protective immunity following trickle infection. In contrast, depletion of group 2 innate lymphoid cells did not alter protective immunity. T. muris trickle infection resulted in a dysbiotic mircrobiota which began to recover alpha diversity following the development of resistance. These data establish trickle infection as a robust and informative model for analysis of immunity to chronic intestinal helminth infection more akin to that observed under natural infection conditions and confirms the importance of CD4+ T cell adaptive immunity in host protection.

  • trickle infection and immunity to Trichuris muris
    bioRxiv, 2019
    Co-Authors: Maya Glover, David J Thornton, Stefano A P Colombo, Richard K Grencis
    Abstract:

    Abstract The majority of experiments investigating the immune response to gastrointestinal helminth infection use a single bolus infection. However, in situ individuals are repeatedly infected with low doses. Therefore, to model natural infection, mice were repeatedly infected (trickle infection) with low doses of Trichuris muris. Trickle infection resulted in the slow acquisition of immunity reflected by a gradual increase in worm burden followed by a partial expulsion. Flow cytometry revealed that the CD4+ T cell response shifted from Th1 dominated to Th2 dominated, which coincided with an increase in Type 2 cytokines. The development of resistance following trickle infection was associated with increased worm expulsion effector mechanisms including goblet cell hyperplasia, Muc5ac production and increased epithelial cell turn over. Depletion of CD4+ T cells reversed resistance confirming their importance in protective immunity following trickle infection. In contrast, depletion of group 2 innate lymphoid cells did not alter protective immunity. T. muris trickle infection resulted in a dysbiotic mircrobiota which began to recover alpha diversity following the development of resistance. These data support trickle infection as a robust and informative model for analysis of immunity to chronic intestinal helminth infection more akin to that observed under natural infection conditions and confirms the importance of CD4+ T cell adaptive immunity in host protection. Author Summary Infection with parasitic worms (helminths) is a considerable cause of morbidity in humans. Understanding how we respond to infection is crucial to developing novel therapies. Laboratory models of helminth infection have been a valuable tool in understanding fundamental immune responses to infection. However, typically an individual mouse will be infected with a large, single-dose of the parasite. This is in contrast to the natural scenario in which individuals will receive frequent low level exposures. What is unknown is how repeated infection alters the development of immunity to infection. We have developed a laboratory model to tackle this question. We infected mice with the model helminth Trichuris muris on a weekly basis and assessed a range of responses in comparison with a more traditional infection system. We found striking differences in the dynamics of the infection, the host immune response, and in changes to host gut microbial populations. Our study shows how resistance to helminth infection can develop over time in response to repeat infection, and provides a model system that better reflects human immunity to this parasite.

Ruth Forman - One of the best experts on this subject based on the ideXlab platform.

  • Trichuris muris infection drives cell intrinsic il4r alpha independent colonic relmα macrophages
    PLOS Pathogens, 2021
    Co-Authors: Ruth Forman, Larisa Logunova, Hannah Smith, Kelly Wemyss, Iris Mair, Louis Boon, Judith E Allen, Werner Muller, Joanne L Pennock, Kathryn J. Else
    Abstract:

    The intestinal nematode parasite Trichuris muris dwells in the caecum and proximal colon driving an acute resolving intestinal inflammation dominated by the presence of macrophages. Notably, these macrophages are characterised by their expression of RELMα during the resolution phase of the infection. The RELMα+ macrophage phenotype associates with the presence of alternatively activated macrophages and work in other model systems has demonstrated that the balance of classically and alternatively activated macrophages is critically important in enabling the resolution of inflammation. Moreover, in the context of type 2 immunity, RELMα+ alternatively activated macrophages are associated with the activation of macrophages via the IL4Rα. Despite a breadth of inflammatory pathologies associated with the large intestine, including those that accompany parasitic infection, it is not known how colonic macrophages are activated towards an alternatively activated phenotype. Here, we address this important knowledge gap by using Trichuris muris infection, in combination with transgenic mice (IL4Rαfl/fl.CX3CR1Cre) and IL4Rα-deficient/wild-type mixed bone marrow chimaeras. We make the unexpected finding that education of colonic macrophages towards a RELMα+, alternatively activated macrophage phenotype during T. muris infection does not require IL4Rα expression on macrophages. Further, this independence is maintained even when the mice are treated with an anti-IFNγ antibody during infection to create a strongly polarised Th2 environment. In contrast to RELMα, PD-L2 expression on macrophages post infection was dependent on IL4Rα signalling in the macrophages. These novel data sets are important, revealing a surprising cell-intrinsic IL4R alpha independence of the colonic RELMα+ alternatively activated macrophage during Trichuris muris infection.

  • Trichuris muris as a tool for holistic discovery research from translational research to environmental bio tagging
    Parasitology, 2021
    Co-Authors: Iris Mair, Kathryn J. Else, Ruth Forman
    Abstract:

    Trichuris spp. (whipworms) are intestinal nematode parasites which cause chronic infections associated with significant morbidities. Trichuris muris in a mouse is the most well studied of the whipworms and research on this species has been approached from a number of different disciplines. Research on T. muris in a laboratory mouse has provided vital insights into the host–parasite interaction through analyses of the immune responses to infection, identifying factors underpinning host susceptibility and resistance. Laboratory studies have also informed strategies for disease control through anthelmintics and vaccine research. On the contrary, research on naturally occurring infections with Trichuris spp. allows the analysis of the host–parasite co-evolutionary relationships and parasite genetic diversity. Furthermore, ecological studies utilizing Trichuris have aided our knowledge of the intricate relationships amongst parasite, host and environment. More recently, studies in wild and semi-wild settings have combined the strengths of the model organism of the house mouse with the complexities of context-dependent physiological responses to infection. This review celebrates the extraordinarily broad range of beneficiaries of whipworm research, from immunologists and parasitologists, through epidemiologists, ecologists and evolutionary biologists to the veterinary and medical communities.

  • structural requirements for dihydrobenzoxazepinone anthelmintics actions against medically important and model parasites Trichuris muris brugia malayi heligmosomoides polygyrus and schistosoma mansoni
    bioRxiv, 2021
    Co-Authors: F A Partridge, Carole J R Bataille, Ruth Forman, A E Marriott, C Haberli, R L Dinsdale, Josephine Fordethomas, James Osullivan, Nicky J Willis
    Abstract:

    Nine hundred million people are infected with the soil-transmitted helminths Ascaris lumbricoides (roundworm), hookworm, and Trichuris trichiura (whipworm). However, low single-dose cure rates of the benzimidazole drugs, the mainstay of preventative chemotherapy for whipworm, together with parasite drug resistance, mean that current approaches may not be able to eliminate morbidity from Trichuriasis. We are seeking to develop new anthelmintic drugs specifically with activity against whipworm as a priority, and previously identified a hit series of dihydrobenzoxazepinone (DHB) compounds that block motility of ex vivo Trichuris muris. Here we report a systematic investigation of the structure-activity relationship of the anthelmintic activity of DHB compounds. We synthesised 47 analogues, which allowed us to define features of the molecules essential for anthelmintic action, as well as broadening the chemotype by identification of dihydrobenzoquinolinones (DBQ) with anthelmintic activity. We investigated the activity of these compounds against other parasitic nematodes, identifying DHB compounds with activity against Brugia malayi and Heligmosomoides polygyrus. We also demonstrated activity of DHB compounds against the trematode Schistosoma mansoni, a parasite that causes schistosomiasis. These results demonstrate the potential of DHB and DBQ compounds for further development as broad-spectrum anthelmintics.

  • structural requirements for dihydrobenzoxazepinone anthelmintics actions against medically important and model parasites Trichuris muris brugia malayi and heligmosomoides polygyrus
    bioRxiv, 2020
    Co-Authors: F A Partridge, Carole J R Bataille, Ruth Forman, A E Marriott, C Haberli, R L Dinsdale, J D Osullivan, Nicky J Willis, J Archer, A Steven
    Abstract:

    Nine hundred million people are infected with the soil-transmitted helminths Ascaris lumbricoides (roundworm), hookworm, and Trichuris trichiura (whipworm). However low single dose cure rates of the benzimidazole drugs, the mainstay of preventative chemotherapy for whipworm, together with parasite drug resistance, mean that current approaches may not be able to eliminate morbidity from Trichuriasis. We are seeking to develop new anthelmintic drugs specifically with activity against whipworm as a priority, and previously identified a hit series of dihydrobenzoxazepinone (DHB) compounds that block motility of ex vivo Trichuris muris. Here we report a systematic investigation of the structure-activity relationship of the anthelmintic activity of DHB compounds. We synthesised 47 analogues, which allowed us to define essential features of the molecules essential for anthelmintic action, as well as broadening the chemotype by identification of dihydrobenzoquinolinones (DBQ) with anthelmintic activity. We also investigated the activity of these compounds against other parasitic nematodes, identifying DHB compounds with activity against Brugia malayi and Heligmosomoides polygyrus. These results demonstrate the potential of DHB and DBQ compounds for further development as broad-spectrum anthelmintics.

  • investigating the importance of b cells and antibodies during Trichuris muris infection using the igmi mouse
    Journal of Molecular Medicine, 2020
    Co-Authors: Rinal Sahputra, Ruth Forman, Iris Mair, Werner Muller, Emma A Murphy, Muhammad Z H Fadlullah, Ari Waisman, Kathryn J. Else
    Abstract:

    The IgMi mouse has normal B cell development; its B cells express an IgM B cell receptor but cannot class switch or secrete antibody. Thus, the IgMi mouse offers a model system by which to dissect out antibody-dependent and antibody-independent B cell function. Here, we provide the first detailed characterisation of the IgMi mouse post-Trichuris muris (T. muris) infection, describing expulsion phenotype, cytokine production, gut pathology and changes in T regulatory cells, T follicular helper cells and germinal centre B cells, in addition to RNA sequencing (RNA seq) analyses of wild-type littermates (WT) and mutant B cells prior to and post infection. IgMi mice were susceptible to a high-dose infection, with reduced Th2 cytokines and elevated B cell-derived IL-10 in mesenteric lymph nodes (MLN) compared to controls. A low-dose infection regime revealed IgMi mice to have significantly more apoptotic cells in the gut compared to WT mice, but no change in intestinal inflammation. IL-10 levels were again elevated. Collectively, this study showcases the potential of the IgMi mouse as a tool for understanding B cell biology and suggests that the B cell plays both antibody-dependent and antibody-independent roles post high- and low-dose T. muris infection.

Koichi Koyama - One of the best experts on this subject based on the ideXlab platform.

  • bacteria induced hatching of Trichuris muris eggs occurs without direct contact between eggs and bacteria
    Parasitology Research, 2016
    Co-Authors: Koichi Koyama
    Abstract:

    Using three isolates of the murine parasitic nematode Trichuris muris, E, E/J (the E isolate maintained in Japan), and S, I have previously demonstrated that when the embryonated eggs of the E/J and E isolates are incubated with the intestinal bacteria Escherichia coli and Staphylococcus aureus, they are induced to hatch in vitro. However, the eggs of the S isolate are unresponsive to these bacteria. In the present study, I investigated whether direct contact between the embryonated eggs of the E/J and E isolates and bacteria is required to induce their hatching. To do so, a new co-culture system for eggs and bacteria (E. coli or S. aureus) was developed to block any direct contact between the eggs and the bacteria. In the hatching experiment using the new system, when direct contact between the eggs and bacteria was completely prevented, the eggs still hatched. However, the peak levels of hatching without direct contact were about 20 % lower than those with direct contact, and peak hatching occurred later without direct contact. This evidence suggests that hatching occurs without direct contact between the eggs and bacteria, and that unidentified material derived from active bacteria induces the hatching of embryonated eggs of the E/J and E isolates of T. muris in vitro.

  • erratum to bacteria induced hatching of Trichuris muris eggs occurs without direct contact between eggs and bacteria
    Parasitology Research, 2016
    Co-Authors: Koichi Koyama
    Abstract:

    Using three isolates of the murine parasitic nematode Trichuris muris, E, E/J (the E isolate maintained in Japan), and S, I have previously demonstrated that when the embryonated eggs of the E/J and E isolates are incubated with the intestinal bacteria Escherichia coli and Staphylococcus aureus, they are induced to hatch in vitro. However, the eggs of the S isolate are unresponsive to these bacteria. In the present study, I investigated whether direct contact between the embryonated eggs of the E/J and E isolates and bacteria is required to induce their hatching. To do so, a new co-culture system for eggs and bacteria (E. coli or S. aureus) was developed to block any direct contact between the eggs and the bacteria. In the hatching experiment using the new system, when direct contact between the eggs and bacteria was completely prevented, the eggs still hatched. However, the peak levels of hatching without direct contact were about 20 % lower than those with direct contact, and peak hatching occurred later without direct contact. This evidence suggests that hatching occurs without direct contact between the eggs and bacteria, and that unidentified material derived from active bacteria induces the hatching of embryonated eggs of the E/J and E isolates of T. muris in vitro.

  • Evidence for bacteria-independent hatching of Trichuris muris eggs
    Parasitology Research, 2013
    Co-Authors: Koichi Koyama
    Abstract:

    Hatching of infective larvae from embryonated eggs in the intestine is an essential first step in Trichuris infections. There are three isolates of the murine parasitic nematode Trichuris muris : E, E-J (the E isolate maintained in Japan), and S. Incubation of T . muris embryonated eggs with the intestinal bacteria Escherichia coli and Staphylococcus aureus induced in vitro hatching of the eggs, but Enterococcus faecalis failed to induce hatching. Bacteria-induced in vitro hatching of embryonated eggs occurred in the E and E-J isolates, whereas the S isolate was unresponsive to bacteria. T . muris worms recovered from infected mice showed no significant difference between the E-J and S isolates in their infectivity to susceptible B10.BR mice ( P  > 0.05). In vivo hatching of embryonated eggs occurred at 30 min post-infection in the upper and lower halves of the small intestine of ddY mice infected with the E-J or S isolates, and on average, 65 % of embryonated eggs recovered from the upper half of the small intestine were hatched in both the E-J and S isolates. In comparison with Enterococcus , the bacteria E . coli and S . aureus represent relatively minor components of the flora of the upper half of the small intestine of mice. These observations point to the possibility that bacteria-independent hatching might also occur in vivo, at least for the S isolate, and imply the existence of a very different system of induction of hatching in vivo.

  • characteristics and incidence of large eggs in Trichuris muris
    Parasitology Research, 2013
    Co-Authors: Koichi Koyama
    Abstract:

    The production of small numbers of large eggs among the standard-sized eggs of Trichuris trichiura is well known. Large eggs have also been observed in Trichuris muris, but they have not been studied previously. This paper compares the characteristics of the large eggs (LEs, ≥74.5 μm long) and standard-sized eggs (SEs, <74.5 μm long) in cultures of T. muris. Among 112,554 cultured eggs, LEs occurred at very low frequency (0.03 %, i.e., about three large eggs per 104 cultured eggs). Embryonated eggs represented 93.72 % of SEs, but only 25.00 % of LEs were embryonated. Embryonated LEs and SEs contained fully matured larvae. An atypical category of unembryonated egg, which contained an incompletely developed larva, an abnormal larva, or granular components, was common among the LEs. However, similar atypical unembryonated SEs were rarely observed. These observations suggest that the LEs that occur very infrequently in T. muris result from an abnormality of embryonation (larval development).

  • dendritic cell expansion occurs in mesenteric lymph nodes of b10 br mice infected with the murine nematode parasite Trichuris muris
    Parasitology Research, 2005
    Co-Authors: Koichi Koyama
    Abstract:

    Dendritic cells (DCs) are a crucial element in the immune system and bridge innate and adaptive immunity. CD11c+ B220− DCs residing in Peyer’s patches (PPs) have the ability to produce interleukin 10 (IL-10) and induce T helper (Th2) development. Evidence suggests that CD11c+ B220− DCs maintain the gut environment by suppressing Th1 responses with IL-10, resulting in a Th2-dominat gut environment. Th2 effectors are required for protection against the murine nematode parasite Trichuris muris, and thus CD11c+ B220− DCs may be involved in the induction of Th2 cells in T. muris infection. In the present study, the kinetics of CD11c+ B220− DCs were analyzed in mesenteric lymph nodes of B10.BR mice infected with the E-J isolate of T. muris, and the cellular expansion of CD11c+ B220− DCs was also observed. As well, the DC expansion was consistent with the occurrence of worm expulsion augmented by IL-4 and IL-13. The evidence here suggests the involvement of CD11c+ B220− DCs in protective Th2 responses to T. muris infection.

Matthew L Deschoolmeester - One of the best experts on this subject based on the ideXlab platform.

  • the goblet cell is the cellular source of the anti microbial angiogenin 4 in the large intestine post Trichuris muris infection
    PLOS ONE, 2012
    Co-Authors: Ruth Forman, Rebecca J M Hurst, Matthew L Deschoolmeester, Steven H Wright, Alan D Pemberton, Kathryn J. Else
    Abstract:

    Background: Mouse angiogenin 4 (Ang4) has previously been described as a Paneth cell–derived antimicrobial peptide important in epithelial host defence in the small intestine. However, a source for Ang4 in the large intestine, which is devoid of Paneth cells, has not been defined. Methodology/Principal Findings: Analysis was performed on Ang4 expression in colonic tissue by qPCR and immunohistochemistry following infection with the large intestine dwelling helminth parasite Trichuris muris. This demonstrated an increase in expression of the peptide following infection of resistant BALB/c mice. Further, histological analysis of colonic tissue revealed the cellular source of this Ang4 to be goblet cells. To elucidate the mechanism of Ang4 expression immunohistochemistry and qPCR for Ang4 was performed on colonic tissue from T. muris infected mouse mutants. Experiments comparing C3H/HeN and C3H/HeJ mice, which have a natural inactivating mutation of TLR4, revealed that Ang4 expression is TLR4 independent. Subsequent experiments with IL-13 and IL-4 receptor alpha deficient mice demonstrated that goblet cell expression of Ang4 is controlled either directly or indirectly by IL-13. Conclusions: The cellular source of mouse Ang4 in the colon following T. muris infection is the goblet cell and expression is under the control of IL-13.

  • accumulation of eosinophils in intestine draining mesenteric lymph nodes occurs after Trichuris muris infection
    Parasite Immunology, 2011
    Co-Authors: Marcus Svensson, L V Bell, Matthew C Little, Matthew L Deschoolmeester, Richard M Locksley, Kathryn J. Else
    Abstract:

    Eosinophils have recently been demonstrated capable of localizing to lymph nodes that drain mucosal surfaces, in particular during T helper 2 (Th2) responses. Resistance of mice to infection with the gastrointestinal nematode Trichuris muris depends critically on mounting of a Th2 response and represents a useful model system to investigate Th2 responses. Following infection of resistant BALB/c mice with T. muris, we observed accumulation of eosinophils in intestine-draining mesenteric lymph nodes (MLNs). The accumulation of MLN eosinophils was initiated during the second week of infection and peaked during worm expulsion. In contrast, we detected a comparably late and modest increase in eosinophil numbers in the MLNs of infected susceptible AKR mice. MLN eosinophils localized preferentially to the medullary region of the lymph node, displayed an activated phenotype and contributed to the interleukin-4 (IL-4) response in the MLN. Despite this, mice genetically deficient in eosinophils efficiently generated IL-4-expressing CD4+ T cells, produced Th2 cytokines and mediated worm expulsion during primary T. muris infection. Thus, IL-4-expressing eosinophils accumulate in MLNs of T. muris-infected BALB/c mice but are dispensable for worm expulsion and generation of Th2 responses, suggesting a distinct or subtle role of MLN eosinophils in the immune response to T. muris infection.

  • rapid dendritic cell mobilization to the large intestinal epithelium is associated with resistance to Trichuris muris infection
    Journal of Immunology, 2009
    Co-Authors: Sheena M Cruickshank, Marcus Svensson, Matthew C Little, Matthew L Deschoolmeester, Larisa Logunova, Gareth J Howell, Aikaterini Bazakou, Nicholas R English, Matthias Mack, Richard K Grencis
    Abstract:

    The large intestine is a major site of infection and disease, yet little is known about how immunity is initiated within this site and the role of dendritic cells (DCs) in this process. We used the well-established model of Trichuris muris infection to investigate the innate response of colonic DCs in mice that are inherently resistant or susceptible to infection. One day postinfection, there was a significant increase in the number of immature colonic DCs in resistant but not susceptible mice. This increase was sustained at day 7 postinfection in resistant mice when the majority of the DCs were mature. There was no increase in DC numbers in susceptible mice until day 13 postinfection. In resistant mice, most colonic DCs were located in or adjacent to the epithelium postinfection. There were also marked differences in the expression of colonic epithelial chemokines in resistant mice and susceptible mice. Resistant mice had significantly increased levels of epithelium-derived CCL2, CCL3, CCL5, and CCL20 compared with susceptible mice. Furthermore, administering neutralizing CCL5 and CCL20 Abs to resistant mice prevented DC recruitment. This study provides clear evidence of differences in the kinetics of DC responses in hosts inherently resistant and susceptible to infection. DC responses in the colon correlate with resistance to infection. Differences in the production of DC chemotactic chemokines by colonic epithelial cells in response to infection in resistant vs susceptible mice may explain the different kinetics of the DC response.

  • the mannose receptor binds Trichuris muris excretory secretory proteins but is not essential for protective immunity
    Immunology, 2009
    Co-Authors: Matthew L Deschoolmeester, Luisa Martinezpomares, Siamon Gordon, Kathryn J. Else
    Abstract:

    Trichuris muris is a natural mouse model of the human gastrointestinal nematode parasite Trichuris trichiura and it is well established that a T helper type 2-dominated immune response is required for worm expulsion. Macrophages accumulate in the large intestine of mice during infection and these cells are known to express the mannose receptor (MR), which may act as a pattern recognition receptor. The data presented here show for the first time that T. muris excretory/secretory products (E/S) induce bone-marrow-derived macrophages (BMDM) to produce several cytokines and have MR-binding activity. Using alternatively activated BMDM from MR knockout mice it is shown that the production of interleukin-6 partially depends on the MR. Infection of MR knockout mice with T. muris reveals that this receptor is not necessary for the expulsion of the parasite because MR knockout mice expel parasites with the same kinetics as wild-type animals and have similar cytokine responses in the mesenteric lymph nodes. Furthermore, despite acting to reduce serum levels of proinflammatory mediators, absence of the MR does not lead to increased gut inflammation after T. muris infection when assessed by macrophage influx, goblet cell hyperplasia and crypt depth. This work suggests that, despite binding components of T. muris E/S, the MR is not critically involved in the generation of the immune response to this parasite.

  • Immunity to Trichuris muris in the laboratory mouse.
    Journal of Helminthology, 2003
    Co-Authors: Kathryn J. Else, Matthew L Deschoolmeester
    Abstract:

    Of all the laboratory models of intestinal nematode infection, Trichuris muris in the mouse is arguably the most powerful. This is largely due to the fact that the ability to expel this parasite is strain dependent. Thus, most mouse strains readily expel T. muris . However certain mouse strains, and indeed some individuals within particular mouse strains, are unable to mount a protective immune response and harbour long term chronic infections. This unique model thus presents an opportunity to examine the immune events underlying both resistance to infection and persistent infection within the same host species, and in some cases, the same host strain.

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