scholarly journals Muc5ac: a critical component mediating the rejection of enteric nematodes

2011 ◽  
Vol 208 (5) ◽  
pp. 893-900 ◽  
Author(s):  
Sumaira Z. Hasnain ◽  
Christopher M. Evans ◽  
Michelle Roy ◽  
Amanda L. Gallagher ◽  
Kristen N. Kindrachuk ◽  
...  
Keyword(s):  
De Novo ◽  
Trichinella Spiralis ◽  
Nematode Infection ◽  
Nippostrongylus Brasiliensis ◽  
Chronic Infections ◽  
Trichuris Muris ◽  
Intestinal Nematode ◽  
Ifn Γ ◽  
Deficient Mice

De novo expression of Muc5ac, a mucin not normally expressed in the intestinal tract, is induced in the cecum of mice resistant to Trichuris muris infection. In this study, we investigated the role of Muc5ac, which is detected shortly before worm expulsion and is associated with the production of interleukin-13 (IL-13), in resistance to this nematode. Muc5ac-deficient mice were incapable of expelling T. muris from the intestine and harbored long-term chronic infections, despite developing strong TH2 responses. Muc5ac-deficient mice had elevated levels of IL-13 and, surprisingly, an increase in the TH1 cytokine IFN-γ. Because TH1 inflammation is thought to favor chronic nematode infection, IFN-γ was neutralized in vivo, resulting in an even stronger TH2-type immune response. Nevertheless, despite a more robust TH2 effector response, the Muc5ac-deficient mice remained highly susceptible to chronic T. muris infection. Importantly, human MUC5AC had a direct detrimental effect on nematode vitality. Moreover, the absence of Muc5ac caused a significant delay in the expulsion of two other gut-dwelling nematodes (Trichinella spiralis and Nippostrongylus brasiliensis). Thus, for the first time, we identify a single mucin, Muc5ac, as a direct and critical mediator of resistance during intestinal nematode infection.

scholarly journals Chronic Intestinal Nematode Infection Exacerbates Experimental Schistosoma mansoni Infection

2008 ◽  
Vol 76 (12) ◽  
pp. 5802-5809 ◽  
Author(s):  
Quentin D. Bickle ◽  
Julie Solum ◽  
Helena Helmby
Keyword(s):  
Immune Response ◽  
Schistosoma Mansoni ◽  
Gastrointestinal Nematode ◽  
Nematode Infection ◽  
Portal System ◽  
Trichuris Muris ◽  
Intestinal Nematode ◽  
Parasite Infections ◽  
And Migration

ABSTRACT Mixed-parasite infections are common in many parts of the world, but little is known of the effects of concomitant parasite infections on the immune response or on disease progression. We have investigated the in vivo effects of a chronic gastrointestinal nematode infection on the infectivity and development of the immune response against the common trematode helminth Schistosoma mansoni. The data show that mice carrying an established chronic Trichuris muris infection and coinfected with S. mansoni, had significantly higher S. mansoni worm burdens than mice without coinfection. The increase in S. mansoni worm burden was accompanied by a higher egg burden in the liver. Kinetic analysis of S. mansoni establishment indicate reduced trapping of S. mansoni larvae during skin-to-lung migration, with T. muris-induced alterations in lung cytokine expression and inflammatory foci surrounding lung-stage schistosomula, suggesting that the immunomodulatory effects of chronic T. muris infection elicited at the gut mucosal surface extend to other organs and perhaps specifically to other mucosal surfaces. The data show that a preexisting chronic gastrointestinal nematode infection facilitates the survival and migration of S. mansoni schistosomula to the portal system, and as a result, increases the egg burden and associated pathology of S. mansoni infection.

scholarly journals Interleukin (Il)-18 Promotes the Development of Chronic Gastrointestinal Helminth Infection by Downregulating IL-13

2001 ◽  
Vol 194 (3) ◽  
pp. 355-364 ◽  
Author(s):  
Helena Helmby ◽  
Kiyoshi Takeda ◽  
Shizuo Akira ◽  
Richard K. Grencis
Keyword(s):  
Critical Role ◽  
Gastrointestinal Nematode ◽  
Inhibitory Effect ◽  
Trichuris Muris ◽  
Gastrointestinal Helminth ◽  
Th Cell ◽  
Ifn Γ ◽  
In Vivo Treatment ◽  
Deficient Mice

Expulsion of the gastrointestinal nematode Trichuris muris is mediated by a T helper (Th) 2 type response involving interleukin (IL)-4 and IL-13. Here we show that Th1 response–associated susceptibility involves prior activation of IL-18 and caspase-1 followed by IL-12 and interferon (IFN)-γ in the intestine. IL-18–deficient mice are highly resistant to chronic T. muris infection and in vivo treatment of normal mice with recombinant (r)IL-18 suppresses IL-13 and IL-4 secretion but does not affect IFN-γ. In vivo treatment of T. muris–infected IFN-γ–deficient mice with rIL-18 demonstrated that the inhibitory effect of IL-18 on IL-13 secretion is independent of IFN-γ. Hence, IL-18 does not function as an IFN-γ–inducing cytokine during chronic T. muris infection but rather as a direct regulator of Th2 cytokines. These results provide the first demonstration of the critical role of IL-18 in regulating Th cell responses during gastrointestinal nematode infection.

scholarly journals IL-12 gene transfer alters gut physiology and host immunity in nematode-infected mice

2001 ◽  
Vol 281 (1) ◽  
pp. G102-G110 ◽  
Author(s):  
Waliul I. Khan ◽  
Patricia A. Blennerhassett ◽  
Yikang Deng ◽  
Jack Gauldie ◽  
Bruce A. Vallance ◽  
...  
Keyword(s):  
Immune Response ◽  
Goblet Cell ◽  
Recombinant Adenovirus ◽  
Trichinella Spiralis ◽  
Nematode Infection ◽  
Interleukin 12 ◽  
Cell Hyperplasia ◽  
Goblet Cell Hyperplasia ◽  
Worm Expulsion ◽  
Ifn Γ

Immune responses elicited by nematode parasite infections are characterized by T helper 2 (Th2) cell induction. The immunologic basis for changes in intestinal physiology accompanying nematode infection is poorly understood. This study examined whether worm expulsion and associated goblet cell hyperplasia and muscle contractility share a similar immune basis by shifting the response from Th2 to Th1 using interleukin-12 (IL-12) overexpression. We used a single administration of recombinant adenovirus vector expressing IL-12 (Ad5IL-12) in Trichinella spiralis-infected mice. Ad5IL-12 administered 1 day after infection prolonged worm survival and inhibited infection-induced muscle hypercontractility and goblet cell hyperplasia. This was correlated with upregulated interferon-γ (IFN-γ) expression and downregulated IL-13 expression in the muscularis externa layer. We also observed increased IFN-γ production and decreased IL-4 and IL-13 production from in vitro stimulated spleen and mesenteric lymph node cells of infected Ad5IL-12-treated mice. These results indicate that transfer and overexpression of the IL-12 gene during Th2-based nematode infection shifts the immune response toward Th1 and delays worm expulsion. Moreover, the immune response shift abrogated the physiological responses to infection, attenuating both muscle hypercontractility and goblet cell hyperplasia. These findings strongly indicate that worm expulsion, muscle hypercontractility, and goblet cell hyperplasia share a common immunologic basis and may be causally linked.

Host–parasite interactions in rodent nematode infections

2003 ◽  
Vol 77 (2) ◽  
pp. 125-131 ◽  
Author(s):  
Y.R. Mahida
Keyword(s):  
Neutralizing Antibodies ◽  
Host Response ◽  
Trichinella Spiralis ◽  
Host Responses ◽  
Nippostrongylus Brasiliensis ◽  
Trichuris Muris ◽  
Epithelial Phenotype ◽  
Worm Expulsion ◽  
Genetically Manipulated ◽  
Host Parasite

AbstractIn rodents,Trichinella spiralisandNippostrongylus brasiliensisinfect the small intestine andTrichuris murisresides in the colon. The intestinal host response in these animals is characterized by changes in mucosal architecture and inflammation and is associated with worm expulsion. The requirement of T cell-mediated host response in worm expulsion has been demonstrated over many years. Subsequent studies have shown that Th2-type, but not Th1-type, responses mediate resistance to the nematodes. Investigations using neutralizing antibodies and genetically manipulated mice have characterized the contribution of individual Th2-type cytokines in not only worm expulsion, but also specific cellular changes that occur in the mucosa, such as alterations in epithelial phenotype and smooth muscle. There is also increasing appreciation of the contribution of non-bone marrow-derived cells in innate and adaptive host responses in these models.

Basophil effector function and homeostasis during helminth infection

Blood ◽  
2009 ◽  
Vol 113 (12) ◽  
pp. 2816-2825 ◽  
Author(s):  
Caspar Ohnmacht ◽  
David Voehringer
Keyword(s):  
De Novo ◽  
Allergic Inflammation ◽  
Lung Parenchyma ◽  
Effector Function ◽  
Nippostrongylus Brasiliensis ◽  
Helminth Parasites ◽  
Alternatively Activated Macrophages ◽  
Effector Cells ◽  
Worm Expulsion

AbstractBasophils are effector cells of the innate immune system that are associated with allergic inflammation and infections with helminth parasites. However, their development and in vivo functions are largely unknown. Here, we characterize basophil development, turnover, tissue localization, and effector function during infection with the helminth Nippostrongylus brasiliensis. Our results demonstrate that under homeostatic conditions basophils have a lifespan of about 60 hours. N brasiliensis–induced basophilia is caused by increased de novo production of basophils in the bone marrow. Basophils were found near the marginal zone in the red pulp of the spleen, in the lamina propria of the small intestine, and in the lung parenchyma. Activated basophils promoted systemic eosinophilia, were associated with differentiation of alternatively activated macrophages in the lung, and contributed to efficient worm expulsion, demonstrating that basophils play a crucial role as effector cells in type 2 immune responses.

Immunity toTrichuris murisin the laboratory mouse

2003 ◽  
Vol 77 (2) ◽  
pp. 95-98 ◽  
Author(s):  
K.J. Else ◽  
M.L. deSchoolmeester
Keyword(s):  
Laboratory Mouse ◽  
Mouse Strains ◽  
Chronic Infections ◽  
Trichuris Muris ◽  
Intestinal Nematode ◽  
Unique Model ◽  
Resistance To Infection ◽  
Laboratory Models ◽  
Strain Dependent

AbstractOf all the laboratory models of intestinal nematode infection,Trichuris murisin 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 expelT. 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.

dSLIM Immunomodulators Induce Anti-Tumor Responses Both In Vitro and In Vivo.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1727-1727
Author(s):  
Manuel Schmidt ◽  
Javier de Cristobal ◽  
Astrid Sander ◽  
Bernadette Brzezicha ◽  
Sven A. König Merediz ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Tumor Cells ◽  
Neutralizing Antibodies ◽  
De Novo ◽  
Tumor Cell Line ◽  
Control Group ◽  
Γδt Cells ◽  
Ifn Γ

Abstract Cytosine-guanine (CpG) motifs containing oligonucleotides (ODN) are commonly used for immunomodulatory purpose in cancer therapy and for the treatment of allergic diseases since they resemble bacterial DNA and serve as “danger signals”. These CpG-ODNs promote predominately a TH1-response with secretion of IL-12 and IFN-γ, In addition their broad potential includes activation of B-cell proliferation, monocyte stimulation and secretion of IgM and IL-6, and stimulation of plasmacytoid DC to produce IFN-α/-β and thus γδT-cells and NK-cells to express CD69 and secrete IFN-γ. Usually phosphorothioate (PS) modifications are to enhance the stability, but these are leading to several side-effects, like severe organ enlargements, morphological changes and immunosuppression in mice. We designed immunomodulatory molecules based on short covalently-closed dumbbell-like structures (dSLIM) to stabilize the DNA without the otherwise necessary PS-modification. To evaluate the anti-tumor effect of the dSLIM molecules we developed an in vitro anti-tumor assay. This assay uses supernatant from dSLIM-activated human PBMCs for incubation with tumor cells in vitro. We observed increased apoptosis and necrosis of the HT-29 tumor cell line after incubation with supernatant from dSLIM-treated PBMC which was significantly higher than the effect of supernatant from non-treated PBMC. In addition, supernatant from dSLIM-treated PBMC increased the expression of HLA-ABC on the tumor cells, a pre-requisite for tumor cell recognition by the immune system. These effects were confirmed with human HEK293 and murine Renca cell lines. Analyzing the effect with neutralizing antibodies to various apoptosis-related cytokines, we observed a crucial role of IFN-γ but not IFN-α or TNFα. To investigate the anti-tumor effects of dSLIM in vivo, we employed a SKH1 murine model which is prone to spontaneous development of papillomas. Using chemicals for initiation and weekly promotion of de novo papilloma development we compared groups of weekly s.c. or i.p. dSLIM injections, respectively, with the PBS control group. The number of papilloma developing mice was significantly lower in the dSLIM groups and the total number of papillomas on all mice was reduced by approximately 50%. In conclusion, we showed that dSLIM immunomodulators exhibit potent anti-tumor effects in vitro and in vivo.

scholarly journals Intestinal Nematode Infection Ameliorates Experimental Colitis in Mice

2002 ◽  
Vol 70 (11) ◽  
pp. 5931-5937 ◽  
Author(s):  
W. I. Khan ◽  
P. A. Blennerhasset ◽  
A. K. Varghese ◽  
S. K. Chowdhury ◽  
P. Omsted ◽  
...  
Keyword(s):  
Immune Response ◽  
Trichinella Spiralis ◽  
Experimental Colitis ◽  
Developed Countries ◽  
Epidemiological Studies ◽  
Nematode Infection ◽  
Th2 Cells ◽  
Th2 Response ◽  
Th1 Cell ◽  
Intestinal Nematode

ABSTRACT Epidemiological studies suggest that inflammatory bowel disease (IBD) is common in developed countries and rare in countries where intestinal nematode infections are common. T cells are critical in many immune responses, including those associated with IBD and nematode infection. Among the distinct T helper (Th) cell subsets, Th1-type immune response is predominantly associated with Crohn's disease, while many nematode infections generate a strong Th2 response. The reciprocal cross regulation between Th1 and Th2 cells suggests that generation of a Th2 response by nematodes could prevent or reduce the effects of Th1-mediated diseases. In the present study, we investigated the effect of polarizing the immune response toward the Th2 type, using intestinal nematode infection, on subsequent experimental colitis. Mice were infected with the intestinal nematode Trichinella spiralis and allowed to recover before colitis was induced with dinitrobenzene sulfonic acid. The mice were sacrificed postcolitis to assess colonic damage macroscopically, histologically, and by myeloperoxidase (MPO) activity and Th cytokines. Prior nematode infection reduced the severity of colitis both macroscopically and histologically together with a decreased mortality and was correlated with a down-regulation of MPO activity, Th1-type cytokine expression in colonic tissue, and emergence of a Th2-type immune response. These results indicate a protective role of nematode infection in Th1 cell-driven inflammation and prompt consideration of a novel therapeutic strategy in IBD based on immunological distraction.

scholarly journals NKG2D function protects the host from tumor initiation

2005 ◽  
Vol 202 (5) ◽  
pp. 583-588 ◽  
Author(s):  
Mark J. Smyth ◽  
Jeremy Swann ◽  
Erika Cretney ◽  
Nadeen Zerafa ◽  
Wayne M. Yokoyama ◽  
...  
Keyword(s):  
De Novo ◽  
Tumor Formation ◽  
Wild Type ◽  
Experimental Tumor ◽  
Host Protection ◽  
Ligand Expression ◽  
Ifn Γ ◽  
Deficient Mice ◽  
Nkg2d Receptor ◽  
Necrosis Factor

The activation NKG2D receptor has been shown to play an important role in the control of experimental tumor growth and metastases expressing ligands for NKG2D; however, a function for this recognition pathway in host protection from de novo tumorigenesis has never been demonstrated. We show that neutralization of NKG2D enhances the sensitivity of wild-type (WT) C57BL/6 and BALB/c mice to methylcholanthrene (MCA)-induced fibrosarcoma. The importance of the NKG2D pathway was additionally illustrated in mice deficient for either IFN-γ or tumor necrosis factor–related apoptosis-inducing ligand, whereas mice depleted of natural killer cells, T cells, or deficient for perforin did not display any detectable NKG2D phenotype. Furthermore, IL-12 therapy preventing MCA-induced sarcoma formation was also largely dependent on the NKG2D pathway. Although NKG2D ligand expression was variable or absent on sarcomas emerging in WT mice, sarcomas derived from perforin-deficient mice were Rae-1+ and immunogenic when transferred into WT syngeneic mice. These findings suggest an important early role for the NKG2D in controlling and shaping tumor formation.

scholarly journals The C-Type Lectin SIGNR1 Binds Schistosoma mansoni Antigens In Vitro, but SIGNR1-Deficient Mice Have Normal Responses during Schistosome Infection

2008 ◽  
Vol 77 (1) ◽  
pp. 399-404 ◽  
Author(s):  
Sean P. Saunders ◽  
Caitriona M. Walsh ◽  
Jillian L. Barlow ◽  
Niamh E. Mangan ◽  
Philip R. Taylor ◽  
...  
Keyword(s):  
Schistosoma Mansoni ◽  
De Novo ◽  
Immunological Response ◽  
Lectin Receptor ◽  
Intracellular Adhesion Molecule ◽  
Innate Recognition ◽  
Murine Homologue ◽  
Deficient Mice

ABSTRACT The de novo immune response to infectious organisms arises from the innate recognition of pathogen-associated molecular patterns (PAMPs) by the host's pattern recognition receptors (PRRs). As the generation of type 2 cytokine responses by the human trematode parasite Schistosoma mansoni is glycan mediated, there is a particular potential role for a C-type lectin receptor (CLR) to mediate the innate recognition of schistosome PAMPs. One such CLR, dendritic cell-specific intracellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN; CD209), has been shown to recognize glycans expressed by S. mansoni eggs. We show that SIGNR1 (SIGN-related 1; CD209b), a murine homologue of DC-SIGN that is expressed on macrophages, also binds both schistosome-soluble egg antigens and worm antigens in vitro. The generation of schistosome egg-induced pulmonary egg granulomas was not altered in SIGNR1-deficient mice. Following S. mansoni infection, the SIGNR1-deficient mice had an unaltered phenotype with an intact immunological response and no difference in pathology. In this study we demonstrate that although SIGNR1 recognizes S. mansoni antigens in vitro, this CLR is redundant during infection. This study highlights the finding that although there was binding of SIGNR1 to immunogenic factors produced in the S. mansoni life cycle, this recognition does not translate to a functional in vivo role for the PRR during infection.

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