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1.
PLoS One ; 19(7): e0292408, 2024.
Article in English | MEDLINE | ID: mdl-38950025

ABSTRACT

Co-infections are a common reality but understanding how the immune system responds in this context is complex and can be unpredictable. Heligmosomoides bakeri (parasitic roundworm, previously Heligmosomoides polygyrus) and Toxoplasma gondii (protozoan parasite) are well studied organisms that stimulate a characteristic Th2 and Th1 response, respectively. Several studies have demonstrated reduced inflammatory cytokine responses in animals co-infected with such organisms. However, while general cytokine signatures have been examined, the impact of the different cytokine producing lymphocytes on parasite control/clearance is not fully understood. We investigated five different lymphocyte populations (NK, NKT, γδ T, CD4+ T and CD8+ T cells), five organs (small intestine, Peyer's patches, mesenteric lymph nodes, spleen and liver), and 4 cytokines (IFN©, IL-4, IL-10 and IL-13) at two different time points (days 5 and 10 post T. gondii infection). We found that co-infected animals had significantly higher mortality than either single infection. This was accompanied by transient and local changes in parasite loads and cytokine profiles. Despite the early changes in lymphocyte and cytokine profiles, severe intestinal pathology in co-infected mice likely contributed to early mortality due to significant damage by both parasites in the small intestine. Our work demonstrates the importance of taking a broad view during infection research, studying multiple cell types, organs/tissues and time points to link and/or uncouple immunological from pathological findings. Our results provide insights into how co-infection with parasites stimulating different arms of the immune system can lead to drastic changes in infection dynamics.


Subject(s)
Coinfection , Cytokines , Nematospiroides dubius , Toxoplasma , Animals , Coinfection/immunology , Coinfection/parasitology , Toxoplasma/immunology , Mice , Cytokines/metabolism , Nematospiroides dubius/immunology , Strongylida Infections/immunology , Strongylida Infections/parasitology , Strongylida Infections/mortality , Toxoplasmosis/immunology , Toxoplasmosis/mortality , Toxoplasmosis/complications , Female , Toxoplasmosis, Animal/immunology , Toxoplasmosis, Animal/mortality , Toxoplasmosis, Animal/parasitology , Spleen/immunology , Spleen/pathology , Spleen/parasitology , Parasite Load , Lymphoid Tissue/immunology , Lymphoid Tissue/pathology , Lymphoid Tissue/parasitology
2.
Nat Commun ; 15(1): 5226, 2024 Jun 19.
Article in English | MEDLINE | ID: mdl-38890291

ABSTRACT

IL-33 plays a significant role in inflammation, allergy, and host defence against parasitic helminths. The model gastrointestinal nematode Heligmosomoides polygyrus bakeri secretes the Alarmin Release Inhibitor HpARI2, an effector protein that suppresses protective immune responses and asthma in its host by inhibiting IL-33 signalling. Here we reveal the structure of HpARI2 bound to mouse IL-33. HpARI2 contains three CCP-like domains, and we show that it contacts IL-33 primarily through the second and third of these. A large loop which emerges from CCP3 directly contacts IL-33 and structural comparison shows that this overlaps with the binding site on IL-33 for its receptor, ST2, preventing formation of a signalling complex. Truncations of HpARI2 which lack the large loop from CCP3 are not able to block IL-33-mediated signalling in a cell-based assay and in an in vivo female mouse model of asthma. This shows that direct competition between HpARI2 and ST2 is responsible for suppression of IL-33-dependent responses.


Subject(s)
Asthma , Helminth Proteins , Interleukin-1 Receptor-Like 1 Protein , Interleukin-33 , Nematospiroides dubius , Animals , Interleukin-33/metabolism , Interleukin-33/chemistry , Nematospiroides dubius/immunology , Helminth Proteins/metabolism , Helminth Proteins/chemistry , Helminth Proteins/immunology , Mice , Female , Interleukin-1 Receptor-Like 1 Protein/metabolism , Asthma/immunology , Asthma/metabolism , Humans , Signal Transduction , Strongylida Infections/immunology , Strongylida Infections/parasitology , Strongylida Infections/metabolism , Protein Binding , Disease Models, Animal , Binding Sites , Mice, Inbred BALB C , Mice, Inbred C57BL
3.
Gut Microbes ; 16(1): 2370917, 2024.
Article in English | MEDLINE | ID: mdl-38944838

ABSTRACT

Polyphenols are phytochemicals commonly found in plant-based diets which have demonstrated immunomodulatory and anti-inflammatory properties. However, the interplay between polyphenols and pathogens at mucosal barrier surfaces has not yet been elucidated in detail. Here, we show that proanthocyanidin (PAC) polyphenols interact with gut parasites to influence immune function and gut microbial-derived metabolites in mice. PAC intake inhibited mastocytosis during infection with the small intestinal roundworm Heligmosomoides polygyrus, and altered the host tissue transcriptome at the site of infection with the large intestinal whipworm Trichuris muris, with a notable enhancement of type-1 inflammatory and interferon-driven gene pathways. In the absence of infection, PAC intake promoted the expansion of Turicibacter within the gut microbiota, increased fecal short chain fatty acids, and enriched phenolic metabolites such as phenyl-γ-valerolactones in the cecum. However, these putatively beneficial effects were reduced in PAC-fed mice infected with T. muris, suggesting concomitant parasite infection can attenuate gut microbial-mediated PAC catabolism. Collectively, our results suggest an inter-relationship between a phytonutrient and infection, whereby PAC may augment parasite-induced inflammation (most prominently with the cecum dwelling T. muris), and infection may abrogate the beneficial effects of health-promoting phytochemicals.


Subject(s)
Gastrointestinal Microbiome , Nematospiroides dubius , Polyphenols , Proanthocyanidins , Trichuriasis , Trichuris , Animals , Mice , Polyphenols/pharmacology , Polyphenols/metabolism , Trichuris/metabolism , Trichuriasis/parasitology , Trichuriasis/immunology , Nematospiroides dubius/immunology , Proanthocyanidins/metabolism , Proanthocyanidins/pharmacology , Mice, Inbred C57BL , Strongylida Infections/immunology , Strongylida Infections/parasitology , Strongylida Infections/metabolism , Female , Bacteria/classification , Bacteria/metabolism , Bacteria/genetics , Bacteria/isolation & purification , Feces/parasitology , Feces/microbiology
4.
Immunity ; 57(6): 1260-1273.e7, 2024 Jun 11.
Article in English | MEDLINE | ID: mdl-38744292

ABSTRACT

Upon parasitic helminth infection, activated intestinal tuft cells secrete interleukin-25 (IL-25), which initiates a type 2 immune response during which lamina propria type 2 innate lymphoid cells (ILC2s) produce IL-13. This causes epithelial remodeling, including tuft cell hyperplasia, the function of which is unknown. We identified a cholinergic effector function of tuft cells, which are the only epithelial cells that expressed choline acetyltransferase (ChAT). During parasite infection, mice with epithelial-specific deletion of ChAT had increased worm burden, fitness, and fecal egg counts, even though type 2 immune responses were comparable. Mechanistically, IL-13-amplified tuft cells release acetylcholine (ACh) into the gut lumen. Finally, we demonstrated a direct effect of ACh on worms, which reduced their fecundity via helminth-expressed muscarinic ACh receptors. Thus, tuft cells are sentinels in naive mice, and their amplification upon helminth infection provides an additional type 2 immune response effector function.


Subject(s)
Acetylcholine , Intestinal Mucosa , Animals , Acetylcholine/metabolism , Mice , Intestinal Mucosa/immunology , Intestinal Mucosa/metabolism , Intestinal Mucosa/parasitology , Choline O-Acetyltransferase/metabolism , Interleukin-13/metabolism , Interleukin-13/immunology , Mice, Knockout , Mice, Inbred C57BL , Helminthiasis/immunology , Helminthiasis/parasitology , Epithelial Cells/immunology , Epithelial Cells/metabolism , Immunity, Innate , Nematospiroides dubius/immunology , Tuft Cells
5.
Immunol Cell Biol ; 102(5): 396-406, 2024.
Article in English | MEDLINE | ID: mdl-38648862

ABSTRACT

Increased permeability of the intestinal epithelial layer is linked to the pathogenesis and perpetuation of a wide range of intestinal and extra-intestinal diseases. Infecting humans with controlled doses of helminths, such as human hookworm (termed hookworm therapy), is proposed as a treatment for many of the same diseases. Helminths induce immunoregulatory changes in their host which could decrease epithelial permeability, which is highlighted as a potential mechanism through which helminths treat disease. Despite this, the influence of a chronic helminth infection on epithelial permeability remains unclear. This study uses the chronically infecting intestinal helminth Heligmosomoides polygyrus to reveal alterations in the expression of intestinal tight junction proteins and epithelial permeability during the infection course. In the acute infection phase (1 week postinfection), an increase in intestinal epithelial permeability is observed. Consistent with this finding, jejunal claudin-2 is upregulated and tricellulin is downregulated. By contrast, in the chronic infection phase (6 weeks postinfection), colonic claudin-1 is upregulated and epithelial permeability decreases. Importantly, this study also investigates changes in epithelial permeability in a small human cohort experimentally challenged with the human hookworm, Necator americanus. It demonstrates a trend toward small intestinal permeability increasing in the acute infection phase (8 weeks postinfection), and colonic and whole gut permeability decreasing in the chronic infection phase (24 weeks postinfection), suggesting a conserved epithelial response between humans and mice. In summary, our findings demonstrate dynamic changes in epithelial permeability during a chronic helminth infection and provide another plausible mechanism by which chronic helminth infections could be utilized to treat disease.


Subject(s)
Intestinal Mucosa , Permeability , Animals , Humans , Intestinal Mucosa/parasitology , Intestinal Mucosa/metabolism , Intestinal Mucosa/immunology , Chronic Disease , Nematospiroides dubius/immunology , Mice , Necator americanus , Intestinal Diseases, Parasitic/immunology , Tight Junctions/metabolism , Tight Junction Proteins/metabolism , Intestine, Small/parasitology , Intestine, Small/immunology , Female , Mice, Inbred C57BL , Male , Helminthiasis/immunology , Helminthiasis/parasitology , Necatoriasis/immunology , MARVEL Domain Containing 2 Protein/metabolism
6.
Nature ; 607(7917): 142-148, 2022 07.
Article in English | MEDLINE | ID: mdl-35732734

ABSTRACT

The divergence of the common dendritic cell progenitor1-3 (CDP) into the conventional type 1 and type 2 dendritic cell (cDC1 and cDC2, respectively) lineages4,5 is poorly understood. Some transcription factors act in the commitment of already specified progenitors-such as BATF3, which stabilizes Irf8 autoactivation at the +32 kb Irf8 enhancer4,6-but the mechanisms controlling the initial divergence of CDPs remain unknown. Here we report the transcriptional basis of CDP divergence and describe the first requirements for pre-cDC2 specification. Genetic epistasis analysis7 suggested that Nfil3 acts upstream of Id2, Batf3 and Zeb2 in cDC1 development but did not reveal its mechanism or targets. Analysis of newly generated NFIL3 reporter mice showed extremely transient NFIL3 expression during cDC1 specification. CUT&RUN and chromatin immunoprecipitation followed by sequencing identified endogenous NFIL3 binding in the -165 kb Zeb2 enhancer8 at three sites that also bind the CCAAT-enhancer-binding proteins C/EBPα and C/EBPß. In vivo mutational analysis using CRISPR-Cas9 targeting showed that these NFIL3-C/EBP sites are functionally redundant, with C/EBPs supporting and NFIL3 repressing Zeb2 expression at these sites. A triple mutation of all three NFIL3-C/EBP sites ablated Zeb2 expression in myeloid, but not lymphoid progenitors, causing the complete loss of pre-cDC2 specification and mature cDC2 development in vivo. These mice did not generate T helper 2 (TH2) cell responses against Heligmosomoides polygyrus infection, consistent with cDC2 supporting TH2 responses to helminths9-11. Thus, CDP divergence into cDC1 or cDC2 is controlled by competition between NFIL3 and C/EBPs at the -165 kb Zeb2 enhancer.


Subject(s)
Cell Differentiation , Dendritic Cells , Enhancer Elements, Genetic , Mutation , Zinc Finger E-box Binding Homeobox 2 , Animals , Basic-Leucine Zipper Transcription Factors/metabolism , CCAAT-Enhancer-Binding Proteins/metabolism , Cell Differentiation/genetics , Dendritic Cells/classification , Dendritic Cells/cytology , Dendritic Cells/pathology , Enhancer Elements, Genetic/genetics , Epistasis, Genetic , Inhibitor of Differentiation Protein 2 , Lymphocytes/cytology , Mice , Myeloid Cells/cytology , Nematospiroides dubius/immunology , Repressor Proteins , Th2 Cells/cytology , Th2 Cells/immunology , Zinc Finger E-box Binding Homeobox 2/genetics
7.
J Biol Chem ; 298(6): 101994, 2022 06.
Article in English | MEDLINE | ID: mdl-35500648

ABSTRACT

The mouse intestinal helminth Heligmosomoides polygyrus modulates host immune responses by secreting a transforming growth factor (TGF)-ß mimic (TGM), to expand the population of Foxp3+ Tregs. TGM comprises five complement control protein (CCP)-like domains, designated D1-D5. Though lacking homology to TGF-ß, TGM binds directly to the TGF-ß receptors TßRI and TßRII and stimulates the differentiation of naïve T-cells into Tregs. However, the molecular determinants of binding are unclear. Here, we used surface plasmon resonance, isothermal calorimetry, NMR spectroscopy, and mutagenesis to investigate how TGM binds the TGF-ß receptors. We demonstrate that binding is modular, with D1-D2 binding to TßRI and D3 binding to TßRII. D1-D2 and D3 were further shown to compete with TGF-ß(TßRII)2 and TGF-ß for binding to TßRI and TßRII, respectively. The solution structure of TGM-D3 revealed that TGM adopts a CCP-like fold but is also modified to allow the C-terminal strand to diverge, leading to an expansion of the domain and opening potential interaction surfaces. TGM-D3 also incorporates a long structurally ordered hypervariable loop, adding further potential interaction sites. Through NMR shift perturbations and binding studies of TGM-D3 and TßRII variants, TGM-D3 was shown to occupy the same site of TßRII as bound by TGF-ß using both a novel interaction surface and the hypervariable loop. These results, together with the identification of other secreted CCP-like proteins with immunomodulatory activity in H. polygyrus, suggest that TGM is part of a larger family of evolutionarily plastic parasite effector molecules that mediate novel interactions with their host.


Subject(s)
Helminth Proteins , Host-Pathogen Interactions , Nematospiroides dubius , Receptors, Transforming Growth Factor beta , Transforming Growth Factor beta , Animals , Biological Evolution , Helminth Proteins/genetics , Helminth Proteins/immunology , Host-Pathogen Interactions/immunology , Mice , Nematospiroides dubius/classification , Nematospiroides dubius/genetics , Nematospiroides dubius/immunology , Nematospiroides dubius/metabolism , Protein Binding , Receptors, Transforming Growth Factor beta/metabolism , T-Lymphocytes, Regulatory/metabolism , Transforming Growth Factor beta/metabolism
8.
Nature ; 599(7883): 125-130, 2021 11.
Article in English | MEDLINE | ID: mdl-34671159

ABSTRACT

Tissue maintenance and repair depend on the integrated activity of multiple cell types1. Whereas the contributions of epithelial2,3, immune4,5 and stromal cells6,7 in intestinal tissue integrity are well understood, the role of intrinsic neuroglia networks remains largely unknown. Here we uncover important roles of enteric glial cells (EGCs) in intestinal homeostasis, immunity and tissue repair. We demonstrate that infection of mice with Heligmosomoides polygyrus leads to enteric gliosis and the upregulation of an interferon gamma (IFNγ) gene signature. IFNγ-dependent gene modules were also induced in EGCs from patients with inflammatory bowel disease8. Single-cell transcriptomics analysis of the tunica muscularis showed that glia-specific abrogation of IFNγ signalling leads to tissue-wide activation of pro-inflammatory transcriptional programs. Furthermore, disruption of the IFNγ-EGC signalling axis enhanced the inflammatory and granulomatous response of the tunica muscularis to helminths. Mechanistically, we show that the upregulation of Cxcl10 is an early immediate response of EGCs to IFNγ signalling and provide evidence that this chemokine and the downstream amplification of IFNγ signalling in the tunica muscularis are required for a measured inflammatory response to helminths and resolution of the granulomatous pathology. Our study demonstrates that IFNγ signalling in enteric glia is central to intestinal homeostasis and reveals critical roles of the IFNγ-EGC-CXCL10 axis in immune response and tissue repair after infectious challenge.


Subject(s)
Homeostasis , Intestines/immunology , Intestines/physiology , Neuroglia/immunology , Neuroglia/physiology , Regeneration , Adventitia/immunology , Adventitia/parasitology , Animals , Chemokine CXCL10/immunology , Duodenum/immunology , Duodenum/parasitology , Duodenum/pathology , Duodenum/physiology , Female , Gliosis , Homeostasis/immunology , Humans , Inflammation/immunology , Inflammation/pathology , Interferon-gamma/immunology , Intestines/parasitology , Intestines/pathology , Male , Mice , Nematospiroides dubius/immunology , Nematospiroides dubius/pathogenicity , Signal Transduction/immunology , Strongylida Infections/immunology , Strongylida Infections/parasitology , Strongylida Infections/pathology
9.
Indian J Tuberc ; 68(3): 340-349, 2021 Jul.
Article in English | MEDLINE | ID: mdl-34099199

ABSTRACT

BACKGROUND: Tuberculosis is a chronic infection caused by Mycobacterium tuberculosis (M.tb), which needs proper macrophage activation for control. It has been debated whether the co-infection with helminth will affect the immune response to mycobacterial infection. OBJECTIVE: To determine the effect of sequential co-infection of Heligmosomoides polygyrus (H.pg) nematodes and M.tb on T cell responses, macrophages polarization and lung histopathological changes. METHOD: This study used 49 mice divided into 7 treatment groups, with different sequence of infection of M.tb via inhalation and H.pg via oral ingestion for 8 and 16 weeks. T cells response in the lung, intestine, and peripheral blood were determined by flow cytometry. Cytokines (IL-4, IFN-γ, TGB-ß1, and IL-10) were measured in peripheral blood using ELISA. Lung macrophage polarization were determined by the expression of iNOS (M1) or Arginase 1 (M2). Mycobacterial count were done in lung tissue. Lung histopathology were measured using Dorman's semiquantitative score assessing peribronchiolitis, perivasculitis, alveolitis, and granuloma formation. RESULT: M.tb infection induced Th1 response and M1 macrophage polarization, while H.pg infection induced Th2 and M2 polarization. In sequential co-infection, the final polarization of macrophage was dictated by the sequence of co-infection. However, all groups with M.tb infection showed the same degree of mycobacterial count in lung tissues and lung tissue histopathological changes. CONCLUSION: Sequential co-infection of H.pg and M.tb induces different T cell response which leads to different macrophage polarization in lung tissue. Helminth infection induced M2 lung macrophage polarization, but did not cause different mycobacterial count nor lung histopathological changes.


Subject(s)
Lung , Macrophage Activation/immunology , Macrophages, Alveolar/immunology , Mycobacterium tuberculosis/immunology , Nematospiroides dubius/immunology , Strongylida Infections , Tuberculosis , Animals , Cell Count , Cell Polarity/immunology , Coinfection/immunology , Coinfection/microbiology , Coinfection/parasitology , Cytokines/blood , Disease Models, Animal , Immunity, Cellular , Lung/immunology , Lung/pathology , Mice , Strongylida Infections/immunology , Strongylida Infections/parasitology , T-Lymphocytes/immunology , Tuberculosis/immunology , Tuberculosis/microbiology
10.
Front Immunol ; 12: 627638, 2021.
Article in English | MEDLINE | ID: mdl-33936040

ABSTRACT

Background: Tuberculosis (TB) is still a major challenge for humankind. Because regions with the highest incidence also have a high prevalence of helminthiasis and nutritional scarcity, we wanted to understand the impact of these on TB progression. Methods: We have developed an experimental murine model for active TB in C3HeB/FeJ, coinfected with Trichuris muris and Heligmosomoides polygyrus nematodes, and exposed to an environmental mycobacterium (M. manresensis) and intermittent fasting. Cause-effect relationships among these factors were explored with Partial Least Squares Path modelling (PLSPM). Results: Previous parasitization had a major anti-inflammatory effect and reduced systemic levels of ADA, haptoglobin, local pulmonary levels of IL-1ß, IL-6, TNF-α, CXCL-1, CXCL-5 and IL-10. Oral administration of heat-killed M. manresensis resulted in a similar outcome. Both interventions diminished pulmonary pathology and bacillary load, but intermittent food deprivation reduced this protective effect increasing stress and inflammation. The PLSPM revealed nematodes might have protective effects against TB progression. Conclusions: Significantly higher cortisol levels in food-deprivation groups showed it is a stressful condition, which might explain its deleterious effect. This highlights the impact of food security on TB eradication policies and the need to prioritize food supply over deworming activities.


Subject(s)
Coinfection , Food Deprivation , Helminthiasis/parasitology , Intestinal Diseases, Parasitic/parasitology , Lung/microbiology , Mycobacterium tuberculosis/pathogenicity , Nematospiroides dubius/pathogenicity , Strongylida Infections/parasitology , Trichuriasis/parasitology , Trichuris/pathogenicity , Tuberculosis, Pulmonary/microbiology , Animal Nutritional Physiological Phenomena , Animals , Cytokines/metabolism , Disease Models, Animal , Disease Progression , Female , Helminthiasis/immunology , Helminthiasis/metabolism , Host-Parasite Interactions , Inflammation Mediators/metabolism , Intestinal Diseases, Parasitic/immunology , Intestinal Diseases, Parasitic/metabolism , Lung/immunology , Lung/metabolism , Male , Mice, Inbred C3H , Mycobacterium tuberculosis/immunology , Nematospiroides dubius/immunology , Nutritional Status , Strongylida Infections/immunology , Strongylida Infections/metabolism , Trichuriasis/immunology , Trichuriasis/metabolism , Trichuris/immunology , Tuberculosis, Pulmonary/immunology , Tuberculosis, Pulmonary/metabolism
11.
Nat Immunol ; 22(2): 216-228, 2021 02.
Article in English | MEDLINE | ID: mdl-33462454

ABSTRACT

CD4+ effector lymphocytes (Teff) are traditionally classified by the cytokines they produce. To determine the states that Teff cells actually adopt in frontline tissues in vivo, we applied single-cell transcriptome and chromatin analyses to colonic Teff cells in germ-free or conventional mice or in mice after challenge with a range of phenotypically biasing microbes. Unexpected subsets were marked by the expression of the interferon (IFN) signature or myeloid-specific transcripts, but transcriptome or chromatin structure could not resolve discrete clusters fitting classic helper T cell (TH) subsets. At baseline or at different times of infection, transcripts encoding cytokines or proteins commonly used as TH markers were distributed in a polarized continuum, which was functionally validated. Clones derived from single progenitors gave rise to both IFN-γ- and interleukin (IL)-17-producing cells. Most of the transcriptional variance was tied to the infecting agent, independent of the cytokines produced, and chromatin variance primarily reflected activities of activator protein (AP)-1 and IFN-regulatory factor (IRF) transcription factor (TF) families, not the canonical subset master regulators T-bet, GATA3 or RORγ.


Subject(s)
Bacteria/pathogenicity , Bacterial Infections/microbiology , CD4-Positive T-Lymphocytes/microbiology , CD4-Positive T-Lymphocytes/parasitology , Colon/microbiology , Colon/parasitology , Gastrointestinal Microbiome , Heligmosomatoidea/pathogenicity , Intestinal Diseases, Parasitic/parasitology , Animals , Bacteria/immunology , Bacterial Infections/genetics , Bacterial Infections/immunology , Bacterial Infections/metabolism , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/metabolism , Chromatin/genetics , Chromatin/metabolism , Citrobacter rodentium/immunology , Citrobacter rodentium/pathogenicity , Colon/immunology , Colon/metabolism , Cytokines/genetics , Cytokines/metabolism , Disease Models, Animal , Gene Expression Profiling , Heligmosomatoidea/immunology , Host-Pathogen Interactions , Interferon Regulatory Factors/genetics , Interferon Regulatory Factors/metabolism , Intestinal Diseases, Parasitic/genetics , Intestinal Diseases, Parasitic/immunology , Intestinal Diseases, Parasitic/metabolism , Male , Mice, Inbred C57BL , Mice, Transgenic , Nematospiroides dubius/immunology , Nematospiroides dubius/pathogenicity , Nippostrongylus/immunology , Nippostrongylus/pathogenicity , Phenotype , Salmonella enterica/immunology , Salmonella enterica/pathogenicity , Single-Cell Analysis , Transcription Factor AP-1/genetics , Transcription Factor AP-1/metabolism , Transcriptome
12.
Eur J Immunol ; 51(2): 433-444, 2021 02.
Article in English | MEDLINE | ID: mdl-33067820

ABSTRACT

Infection with parasitic worms (helminths) alters host immune responses and can inhibit pathogenic inflammation. Helminth infection promotes a strong Th2 and T regulatory response while suppressing Th1 and Th17 function. Th2 responses are largely dependent on transcriptional programs directed by Stat6-signaling. We examined the importance of intact T cell Stat6 signaling on helminth-induced suppression of murine colitis that results from T cell transfer into immune-deficient mice. Colonization with the intestinal nematode Heligmosomoides polygyrus bakeri resolves WT T cell transfer colitis. However, if the transferred T cells lack intact Stat6 then helminth exposure failed to attenuate colitis or suppress MLN T cell IFN-γ or IL17 production. Loss of Stat6 signaling resulted in decreased IL10 and increased IFN-γ co-expression by IL-17+ T cells. We also transferred T cells from mice with constitutive T cell expression of activated Stat6 (Stat6VT). These mice developed a severe eosinophilic colitis that also was not attenuated by helminth infection. These results show that T cell expression of intact but regulated Stat6 signaling is required for helminth infection-associated regulation of pathogenic intestinal inflammation.


Subject(s)
Colitis/immunology , Nematospiroides dubius/immunology , STAT6 Transcription Factor/immunology , Signal Transduction/immunology , Strongylida Infections/immunology , T-Lymphocytes, Regulatory/immunology , Animals , Colitis/parasitology , Interferon-gamma/immunology , Interleukin-10/immunology , Interleukin-17/immunology , Intestinal Mucosa/immunology , Intestinal Mucosa/parasitology , Mice , Mice, Inbred C57BL , Th1 Cells/immunology , Th1 Cells/parasitology , Th17 Cells/immunology , Th17 Cells/parasitology , Th2 Cells/immunology , Th2 Cells/parasitology
13.
Dev Comp Immunol ; 115: 103879, 2021 02.
Article in English | MEDLINE | ID: mdl-33007336

ABSTRACT

The mouse intestinal parasite Heligmosomoides polygyrus demonstrates adaptation to the inflammatory milieu as a result of colitis induced by dextran sulphate sodium (DSS). Nematodes from mice with colitis had different effects on dendritic cells than nematodes from mice without colitis. Immature JAWSII cells pre-exposed to L4 stage H. polygyrus from DSS-treated mice were adoptively transferred to mice with induced colitis. After two days, a higher disease activity index, macroscopic damage score and colon histology score were observed. MLN T cells isolated nine days after transfer demonstrated proinflammatory IFN-γ and IL-17 production. Transfer of JAWSII stimulated with male or female L4 larvae from a control invasion resulted in a slight improvement of colitis; in addition, dendritic cells exposed to H. polygyrus female L4 larvae, provoked migration of CD8+CD25+ T cells from MLN to the colon. Nematodes from an inflammatory environment changed cytokine production by dendritic cells. Inflammatory milieu changing nematode immunomodulatory activity affects dendritic cell functions, which offers new insight into the helminth-host relationship.


Subject(s)
Colitis/therapy , Dendritic Cells/immunology , Nematospiroides dubius/immunology , Therapy with Helminths/methods , Adoptive Transfer , Animals , Cell Movement/immunology , Colitis/chemically induced , Colitis/immunology , Colitis/pathology , Dextran Sulfate/administration & dosage , Dextran Sulfate/toxicity , Disease Models, Animal , Female , Host-Parasite Interactions/immunology , Humans , Intestinal Mucosa/drug effects , Intestinal Mucosa/immunology , Intestinal Mucosa/pathology , Larva , Lymph Nodes/cytology , Lymph Nodes/immunology , Male , Mesentery , Mice , Primary Cell Culture , Sex Factors , T-Lymphocytes/immunology
14.
Sci Immunol ; 5(53)2020 11 13.
Article in English | MEDLINE | ID: mdl-33188058

ABSTRACT

Interleukin-33 (IL-33) is a pleiotropic cytokine that can promote type 2 inflammation but also drives immunoregulation through Foxp3+Treg expansion. How IL-33 is exported from cells to serve this dual role in immunosuppression and inflammation remains unclear. Here, we demonstrate that the biological consequences of IL-33 activity are dictated by its cellular source. Whereas IL-33 derived from epithelial cells stimulates group 2 innate lymphoid cell (ILC2)-driven type 2 immunity and parasite clearance, we report that IL-33 derived from myeloid antigen-presenting cells (APCs) suppresses host-protective inflammatory responses. Conditional deletion of IL-33 in CD11c-expressing cells resulted in lowered numbers of intestinal Foxp3+Treg cells that express the transcription factor GATA3 and the IL-33 receptor ST2, causing elevated IL-5 and IL-13 production and accelerated anti-helminth immunity. We demonstrate that cell-intrinsic IL-33 promoted mouse dendritic cells (DCs) to express the pore-forming protein perforin-2, which may function as a conduit on the plasma membrane facilitating IL-33 export. Lack of perforin-2 in DCs blocked the proliferative expansion of the ST2+Foxp3+Treg subset. We propose that perforin-2 can provide a plasma membrane conduit in DCs that promotes the export of IL-33, contributing to mucosal immunoregulation under steady-state and infectious conditions.


Subject(s)
Dendritic Cells/immunology , Interleukin-33/metabolism , Membrane Proteins/metabolism , Strongylida Infections/immunology , T-Lymphocytes, Regulatory/immunology , Animals , Cell Membrane/metabolism , Chronic Disease , Dendritic Cells/metabolism , Disease Models, Animal , Female , Humans , Immune Tolerance , Immunity, Innate , Immunity, Mucosal , Interleukin-33/analysis , Interleukin-33/genetics , Male , Mice , Mice, Transgenic , Nasal Mucosa/immunology , Nasal Mucosa/pathology , Nasal Polyps/immunology , Nasal Polyps/pathology , Nematospiroides dubius/immunology , Nippostrongylus/immunology , Pore Forming Cytotoxic Proteins , Rhinitis/immunology , Rhinitis/pathology , Sinusitis/immunology , Sinusitis/pathology , Strongylida Infections/parasitology , T-Lymphocytes, Regulatory/metabolism
15.
Front Immunol ; 11: 1830, 2020.
Article in English | MEDLINE | ID: mdl-33117327

ABSTRACT

Helminth parasites are effective in biasing Th2 immunity and inducing regulatory pathways that minimize excessive inflammation within their hosts, thus allowing chronic infection to occur whilst also suppressing bystander atopic or autoimmune diseases. Multiple sclerosis (MS) is a severe autoimmune disease characterized by inflammatory lesions within the central nervous system; there are very limited therapeutic options for the progressive forms of the disease and none are curative. Here, we used the experimental autoimmune encephalomyelitis (EAE) model to examine if the intestinal helminth Heligmosomoides polygyrus and its excretory/secretory products (HES) are able to suppress inflammatory disease. Mice infected with H. polygyrus at the time of immunization with the peptide used to induce EAE (myelin-oligodendrocyte glycoprotein, pMOG), showed a delay in the onset and peak severity of EAE disease, however, treatment with HES only showed a marginal delay in disease onset. Mice that received H. polygyrus 4 weeks prior to EAE induction were also not significantly protected. H. polygyrus secretes a known TGF-ß mimic (Hp-TGM) and simultaneous H. polygyrus infection with pMOG immunization led to a significant expansion of Tregs; however, administering the recombinant Hp-TGM to EAE mice failed to replicate the EAE protection seen during infection, indicating that this may not be central to the disease protecting mechanism. Mice infected with H. polygyrus also showed a systemic Th2 biasing, and restimulating splenocytes with pMOG showed release of pMOG-specific IL-4 as well as suppression of inflammatory IL-17A. Notably, a Th2-skewed response was found only in mice infected with H. polygyrus at the time of EAE induction and not those with a chronic infection. Furthermore, H. polygyrus failed to protect against disease in IL-4Rα-/- mice. Together these results indicate that the EAE disease protective mechanism of H. polygyrus is likely to be predominantly Th2 deviation, and further highlights Th2-biasing as a future therapeutic strategy for MS.


Subject(s)
Antigens, Helminth/immunology , Encephalomyelitis, Autoimmune, Experimental/immunology , Receptors, Cell Surface/immunology , Strongylida Infections/immunology , Th2 Cells/immunology , Animals , Female , Mice , Mice, Inbred C57BL , Mice, Knockout , Nematospiroides dubius/immunology
16.
Int J Mol Sci ; 21(21)2020 Oct 22.
Article in English | MEDLINE | ID: mdl-33105843

ABSTRACT

As the global incidences of colorectal cancer rises, there is a growing importance in understanding the interaction between external factors, such as common infections, on the initiation and progression of this disease. While certain helminth infections have been shown to alter the severity and risk of developing colitis-associated colorectal cancer, whether these parasites can directly affect colorectal cancer progression is unknown. Here, we made use of murine and human colorectal cancer cell lines to demonstrate that exposure to antigens derived from the gastrointestinal nematode Heligmosomoides polygyrus significantly reduced colorectal cancer cell proliferation in vitro. Using a range of approaches, we demonstrate that antigen-dependent reductions in cancer cell proliferation and viability are associated with increased expression of the critical cell cycle regulators p53 and p21. Interestingly, H. polygyrus-derived antigens significantly increased murine colorectal cancer cell migration, which was associated with an increased expression of the adherens junction protein ß-catenin, whereas the opposite was true for human colorectal cancer cells. Together, these findings demonstrate that antigens derived from a gastrointestinal nematode can significantly alter colorectal cancer cell behavior. Further in-depth analysis may reveal novel candidates for targeting and treating late-stage cancer.


Subject(s)
Antigens, Helminth/pharmacology , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , Epithelial-Mesenchymal Transition/drug effects , Nematospiroides dubius/immunology , Animals , Antigens, Helminth/immunology , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Colorectal Neoplasms/genetics , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Epithelial-Mesenchymal Transition/physiology , HCT116 Cells , Humans , Male , Mice, Inbred C57BL , Nematospiroides dubius/metabolism , Schistosoma mansoni/immunology , Schistosomiasis mansoni/immunology , Species Specificity , Tumor Suppressor Protein p53/metabolism , beta Catenin/metabolism
17.
Arch Immunol Ther Exp (Warsz) ; 68(5): 30, 2020 Sep 22.
Article in English | MEDLINE | ID: mdl-32960348

ABSTRACT

An effective host immune system prevents the growth of most cancer cells. However, as intestinal nematodes are able to induce both immunotolerance and immunosuppression in the host, it is possible that their presence could allow co-occurring cancer cells to proliferate and metastasize. Our findings indicate that previous, subsequent or concurrent intestinal nematode infection affects the formation of lung metastatic nodules in mice experimentally infected with Heligmosomoides polygyrus. In addition, pre-infection with nematodes renders mice resistant to metastasis development in lungs, with the inoculated EL4 cancer cells being located mainly in mesenteric lymph nodes. The present paper discusses the nematode-induced mechanisms which may influence the metastatic process.


Subject(s)
Helminthiasis/immunology , Intestinal Diseases, Parasitic/immunology , Lung Neoplasms/secondary , Lymphoma/immunology , Lymphoma/parasitology , Nematospiroides dubius/immunology , Animals , Disease Models, Animal , Immunomodulation , Lung Neoplasms/parasitology , Lymphoma/pathology , Male , Mice , Nematode Infections/immunology , Neoplasm Metastasis , Transforming Growth Factor beta/metabolism
18.
Cell Mol Gastroenterol Hepatol ; 10(4): 763-778, 2020.
Article in English | MEDLINE | ID: mdl-32629118

ABSTRACT

BACKGROUND & AIMS: Epidemiological and animal studies have indicated an inverse correlation between the rising prevalence of obesity and metabolic syndrome and exposure to helminths. Whether helminth-induced immune response contributes to microbiota remodeling in obesity remains unknown. The aim of this study is to explore the immune-regulatory role of helminth in the prevention of HFD-induced obesity through remodeling gut microbiome. METHODS: C57BL/6J WT and STAT6-/- mice were infected with Heligmosomoides polygyrus and followed by high fat diet (HFD) feeding for 6 weeks. The host immune response, body weight, and fecal microbiota composition were analyzed. We used adoptive transfer of M2 macrophages and microbiota transplantation approaches to determine the impact of these factors on HFD-obesity. We also examined stool microbiota composition and short chain fatty acids (SCFAs) concentration and determined the expression of SCFA-relevant receptors in the recipient mice. RESULTS: Helminth infection of STAT6-/- (Th2-deficient) mice and adoptive transfer of helminth-induced alternatively activated (M2) macrophages demonstrated that the helminth-associated Th2 immune response plays an important role in the protection against obesity and induces changes in microbiota composition. Microbiota transplantation showed that helminth-induced, Th2-dependent alterations of the gut microbiota are sufficient to confer protection against obesity. Collectively, these results indicate that helminth infection protects against HFD-induced obesity by Th2-dependent, M2 macrophage-mediated alterations of the intestinal microbiota. CONCLUSION: Our findings provide new mechanistic insights into the complex interplay between helminth infection, the immune system and the gut microbiota in a HFD-induced obesity model and holds promise for gut microbiome-targeted immunotherapy in obesity prevention.


Subject(s)
Diet, High-Fat/adverse effects , Gastrointestinal Microbiome , Nematospiroides dubius/immunology , Obesity/prevention & control , Animals , Cells, Cultured , Mice, Inbred C57BL , Obesity/etiology , Obesity/immunology , Protective Factors , Strongylida Infections/immunology
19.
J Exp Med ; 217(9)2020 09 07.
Article in English | MEDLINE | ID: mdl-32584413

ABSTRACT

Antigen uptake and presentation by naive and germinal center (GC) B cells are different, with the former expressing even low-affinity BCRs efficiently capture and present sufficient antigen to T cells, whereas the latter do so more efficiently after acquiring high-affinity BCRs. We show here that antigen uptake and processing by naive but not GC B cells depend on Cbl and Cbl-b (Cbls), which consequently control naive B and cognate T follicular helper (Tfh) cell interaction and initiation of the GC reaction. Cbls mediate CD79A and CD79B ubiquitination, which is required for BCR-mediated antigen endocytosis and postendocytic sorting to lysosomes, respectively. Blockade of CD79A or CD79B ubiquitination or Cbls ligase activity is sufficient to impede BCR-mediated antigen processing and GC development. Thus, Cbls act at the entry checkpoint of the GC reaction by promoting naive B cell antigen presentation. This regulation may facilitate recruitment of naive B cells with a low-affinity BCR into GCs to initiate the process of affinity maturation.


Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Antigen Presentation/immunology , B-Lymphocytes/immunology , Germinal Center/immunology , Proto-Oncogene Proteins c-cbl/metabolism , Adaptor Proteins, Signal Transducing/deficiency , Adaptor Proteins, Signal Transducing/genetics , Animals , Antibody Formation/immunology , Antigens, CD/metabolism , B-Lymphocytes/cytology , Cell Communication/immunology , Endocytosis , Immunity, Humoral , Intestines/immunology , Intestines/parasitology , Lymphocyte Activation/immunology , Lysosomes/metabolism , Mice, Inbred C57BL , Mutagenesis/genetics , Mutation/genetics , Nematospiroides dubius/immunology , Proto-Oncogene Proteins c-cbl/deficiency , Proto-Oncogene Proteins c-cbl/genetics , Receptors, Antigen, B-Cell/immunology , T-Lymphocytes, Helper-Inducer/cytology , T-Lymphocytes, Helper-Inducer/immunology , Ubiquitination
20.
Elife ; 92020 05 18.
Article in English | MEDLINE | ID: mdl-32420871

ABSTRACT

The IL-33-ST2 pathway is an important initiator of type 2 immune responses. We previously characterised the HpARI protein secreted by the model intestinal nematode Heligmosomoides polygyrus, which binds and blocks IL-33. Here, we identify H. polygyrus Binds Alarmin Receptor and Inhibits (HpBARI) and HpBARI_Hom2, both of which consist of complement control protein (CCP) domains, similarly to the immunomodulatory HpARI and Hp-TGM proteins. HpBARI binds murine ST2, inhibiting cell surface detection of ST2, preventing IL-33-ST2 interactions, and inhibiting IL-33 responses in vitro and in an in vivo mouse model of asthma. In H. polygyrus infection, ST2 detection is abrogated in the peritoneal cavity and lung, consistent with systemic effects of HpBARI. HpBARI_Hom2 also binds human ST2 with high affinity, and effectively blocks human PBMC responses to IL-33. Thus, we show that H. polygyrus blocks the IL-33 pathway via both HpARI which blocks the cytokine, and also HpBARI which blocks the receptor.


Subject(s)
Alternaria/immunology , Antigens, Helminth/metabolism , Asthma/pathology , Interleukin-1 Receptor-Like 1 Protein/antagonists & inhibitors , Interleukin-33/antagonists & inhibitors , Nematospiroides dubius/metabolism , Animals , Cell Line , Humans , Immunologic Factors/metabolism , Interleukin-1 Receptor-Like 1 Protein/metabolism , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Nematospiroides dubius/immunology , Ovalbumin/immunology
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