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Ecotoxicology and Environmental Safety Jun 2024Hydrogen sulphide (HS) is considered an immunotoxicant, and its presence in the water can influence the mucosal barrier functions of fish. However, there is a...
Hydrogen sulphide (HS) is considered an immunotoxicant, and its presence in the water can influence the mucosal barrier functions of fish. However, there is a significant knowledge gap on how fish mucosa responds to low environmental HS levels. The present study investigated the consequences of prolonged exposure to sub-lethal levels of HS on the mucosal defences of Atlantic salmon (Salmo salar). Fish were continuously exposed to two levels of HS (low: 0.05 µM; and high: 0.12 µM) for 12 days. Unexposed fish served as control. Molecular and histological profiling focused on the changes in the skin, gills and olfactory rosette. In addition, metabolomics and proteomics were performed on the skin and gill mucus. The gene expression profile indicated that the gills and olfactory rosette were more sensitive to HS than the skin. The olfactory rosette showed a dose-dependent response, but not the gills. Genes related to stress responses were triggered at mucosal sites by HS. Moreover, HS elicited strong inflammatory responses, particularly in the gills. All mucosal organs demonstrated the key molecular repertoire for sulphide detoxification, but their temporal and spatial expression was not substantially affected by sub-lethal HS levels. Mucosal barrier integrity was not considerably affected by HS. Mucus metabolomes of the skin and gills were unaffected, but a matrix-dependent response was identified. Comparing the high-concentration group's skin and gills mucus metabolomes identified altered amino acid biosynthesis and metabolism pathways. The skin and gill mucus exhibited distinct proteomic profiles. Enrichment analysis revealed that proteins related to immunity and metabolism were affected in both mucus matrices. The present study expands our knowledge of the defence mechanisms against HS at mucosal sites in Atlantic salmon. The findings offer insights into the health and welfare consequences of sub-lethal HS, which can be incorporated into the risk assessment protocols in salmon land-based farms.
PubMed: 38905940
DOI: 10.1016/j.ecoenv.2024.116617 -
Discovery Immunology 2024Direct interaction between T-cells exerts a major influence on tissue immunity and inflammation across multiple body sites including the human gut, which is highly...
Direct interaction between T-cells exerts a major influence on tissue immunity and inflammation across multiple body sites including the human gut, which is highly enriched in 'unconventional' lymphocytes such as γδ T-cells. We previously reported that microbial activation of human Vγ9/Vδ2 γδ T-cells in the presence of the mucosal damage-associated cytokine IL-15 confers the ability to promote epithelial barrier defence, specifically via induction of IL-22 expression in conventional CD4 T-cells. In the current report, we assessed whether other cytokines enriched in the gut milieu also functionally influence microbe-responsive Vγ9/Vδ2 T-cells. When cultured in the presence of IL-21, Vγ9/Vδ2 T-cells acquired the ability to induce expression of the immunoregulatory cytokine IL-10 in both naïve and memory CD4 T-cells, at levels surpassing those induced by monocytes or monocyte-derived DCs. These findings identify an unexpected influence of IL-21 on Vγ9/Vδ2 T-cell modulation of CD4 T-cell responses. Further analyses suggested a possible role for CD30L and/or CD40L reverse signalling in mediating IL-10 induction by IL-21 conditioned Vγ9/Vδ2 T-cells. Our findings indicate that the local microenvironment exerts a profound influence on Vγ9/Vδ2 T-cell responses to microbial challenge, leading to induction of distinct functional profiles among CD4 T-cells that may influence inflammatory events at mucosal surfaces. Targeting these novel pathways may offer therapeutic benefit in disorders such as inflammatory bowel disease.
PubMed: 38903247
DOI: 10.1093/discim/kyae008 -
reshapes mucosal immunity toward a Type 2 response that attenuates inflammatory bowel-like diseases.BioRxiv : the Preprint Server For... Mar 2024Diarrheal diseases are the second leading cause of death in children worldwide. Epidemiological studies show that co-infection with decreases the severity of diarrhea....
Diarrheal diseases are the second leading cause of death in children worldwide. Epidemiological studies show that co-infection with decreases the severity of diarrhea. Here, we show that is highly prevalent in the stools of asymptomatic school-aged children. It orchestrates a Th2 mucosal immune response, characterized by increased antigen-specific Th2 cells, IL-25, Type 2-associated cytokines, and goblet cell hyperplasia. infection expanded IL-10-producing Th2 and GATA3 Treg cells that promoted chronic carriage, parasite transmission, and conferred protection against -induced lethal ileitis and DSS-driven colitis by downregulating proinflammatory cytokines, decreasing Th1/Th17 cell frequency, and preventing collateral tissue damage. Protection was dependent on STAT6 signaling, as -infected STAT6 mice no longer regulated intestinal bystander inflammation. Our findings demonstrate that infection reshapes mucosal immunity toward a Type 2 response, which confers a mutualistic protection against inflammatory disease processes and identifies a critical role for protists in regulating mucosal defenses.
PubMed: 38903060
DOI: 10.1101/2024.03.02.583119 -
Mucosal Immunology Jun 2024Exaggeration of type 2 immune responses promotes lung inflammation and altered lung development; however, eosinophils, despite expansion in the postnatal lung, have not...
Exaggeration of type 2 immune responses promotes lung inflammation and altered lung development; however, eosinophils, despite expansion in the postnatal lung, have not been specifically assessed in the context of neonatal lung disease. Furthermore, early-life factors including prematurity and respiratory infection predispose infants to chronic obstructive pulmonary disease later in life. To assess eosinophils in the developing lung and how they may contribute to chronic lung disease, we generated mice harboring eosinophil-specific deletion of the negative regulatory enzyme SHIP-1. This increased the activity and number of pulmonary eosinophils in the developing lung, which was associated with impaired lung development, expansion of activated alveolar macrophages (AMφ), multinucleated giant cell formation, enlargement of airspaces, and fibrosis. Despite regression of eosinophils following completion of lung development, AMφ-dominated inflammation persisted, alongside lung damage. Bone marrow chimera studies showed that SHIP-1-deficient eosinophils were not sufficient to drive inflammatory lung disease in adult steady-state mice but once inflammation and damage was present, it could not be resolved. Depletion of eosinophils during alveolarization alleviated pulmonary inflammation and lung pathology, demonstrating an eosinophil-intrinsic effect. These results show that the presence of activated eosinophils during alveolarization aggravates AMφs and promotes sustained inflammation and long-lasting lung pathology.
PubMed: 38901764
DOI: 10.1016/j.mucimm.2024.06.003 -
The ISME Journal Jan 2024Probiotics have gained significant attention as a potential strategy to improve health by modulating host-microbe interactions, particularly in situations where the...
Probiotics have gained significant attention as a potential strategy to improve health by modulating host-microbe interactions, particularly in situations where the normal microbiota has been disrupted. However, evidence regarding their efficacy has been inconsistent, with considerable interindividual variability in response. We aimed to explore whether a common genetic variant that affects the production of mucosal α(1,2)-fucosylated glycans, present in around 20% of the population, could explain the observed interpersonal differences in the persistence of commonly used probiotics. Using a mouse model with varying α(1,2)-fucosylated glycans secretion (Fut2WT or Fut2KO), we examined the abundance and persistence of Bifidobacterium strains (infantis, breve, and bifidum). We observed significant differences in baseline gut microbiota characteristics between Fut2WT and Fut2KO littermates, with Fut2WT mice exhibiting enrichment of species able to utilize α(1,2)-fucosylated glycans. Following antibiotic exposure, only Fut2WT animals showed persistent engraftment of Bifidobacterium infantis, a strain able to internalize α(1,2)-fucosylated glycans, whereas B. breve and B. bifidum, which cannot internalize α(1,2)-fucosylated glycans, did not exhibit this difference. In mice with an intact commensal microbiota, the relationship between secretor status and B. infantis persistence was reversed, with Fut2KO animals showing greater persistence compared to Fut2WT. Our findings suggest that the interplay between a common genetic variation and antibiotic exposure plays a crucial role in determining the dynamics of B. infantis in the recipient gut, which could potentially contribute to the observed variation in response to this commonly used probiotic species.
Topics: Animals; Mice; Fucosyltransferases; Gastrointestinal Microbiome; Probiotics; Anti-Bacterial Agents; Galactoside 2-alpha-L-fucosyltransferase; Bifidobacterium longum subspecies infantis; Polysaccharides; Host Microbial Interactions; Mice, Inbred C57BL; Mice, Knockout; Bifidobacterium
PubMed: 38896583
DOI: 10.1093/ismejo/wrae107 -
Microbial Genomics Jun 2024Since the introduction of the 13-valent pneumococcal conjugate vaccine (PCV13) in Malawi in 2011, there has been persistent carriage of vaccine serotype (VT) , despite...
Expansion of pneumococcal serotype 23F and 14 lineages with genotypic changes in capsule polysaccharide locus and virulence gene profiles post introduction of pneumococcal conjugate vaccine in Blantyre, Malawi.
Since the introduction of the 13-valent pneumococcal conjugate vaccine (PCV13) in Malawi in 2011, there has been persistent carriage of vaccine serotype (VT) , despite high vaccine coverage. To determine if there has been a genetic change within the VT capsule polysaccharide (cps) loci since the vaccine's introduction, we compared 1022 whole-genome-sequenced VT isolates from 1998 to 2019. We identified the clonal expansion of a multidrug-resistant, penicillin non-susceptible serotype 23F GPSC14-ST2059 lineage, a serotype 14 GPSC9-ST782 lineage and a novel serotype 14 sequence type GPSC9-ST18728 lineage. Serotype 23F GPSC14-ST2059 had an I253T mutation within the capsule oligosaccharide repeat unit polymerase Wzy protein, which is predicted to alter the protein pocket cavity. Moreover, serotype 23F GPSC14-ST2059 had SNPs in the DNA binding sites for the cps transcriptional repressors CspR and SpxR. Serotype 14 GPSC9-ST782 harbours a non-truncated version of the large repetitive protein (Lrp), containing a Cna protein B-type domain which is also present in proteins associated with infection and colonisation. These emergent lineages also harboured genes associated with antibiotic resistance, and the promotion of colonisation and infection which were absent in other lineages of the same serotype. Together these data suggest that in addition to serotype replacement, modifications of the capsule locus associated with changes in virulence factor expression and antibiotic resistance may promote vaccine escape. In summary, the study highlights that the persistence of vaccine serotype carriage despite high vaccine coverage in Malawi may be partly caused by expansion of VT lineages post-PCV13 rollout.
Topics: Streptococcus pneumoniae; Pneumococcal Vaccines; Humans; Serogroup; Malawi; Bacterial Capsules; Pneumococcal Infections; Vaccines, Conjugate; Polysaccharides, Bacterial; Virulence; Genotype; Whole Genome Sequencing; Bacterial Proteins; Virulence Factors; Child, Preschool; Polymorphism, Single Nucleotide; Infant; Male
PubMed: 38896467
DOI: 10.1099/mgen.0.001264 -
BioRxiv : the Preprint Server For... Jun 2024Treatment strategies for Crohn's disease (CD) suppress diverse inflammatory pathways but many patients remain refractory to treatment. Autologous hematopoietic stem cell...
BACKGROUND
Treatment strategies for Crohn's disease (CD) suppress diverse inflammatory pathways but many patients remain refractory to treatment. Autologous hematopoietic stem cell transplantation (SCT) has emerged as a therapy for medically refractory CD. SCT was developed to rescue cancer patients from myelosuppressive chemotherapy but its use for CD and other immune diseases necessitates reimagining SCT as a cellular therapy that restores appropriately responsive immune cell populations from hematopoietic progenitors in the stem cell autograft (i.e. immune "reset"). Here we present a paradigm to understand SCT as a cellular therapy for immune diseases and reveal how SCT re-establishes cellular immunity utilizing high-dimensional cellular phenotyping and functional studies of the stem cell grafts.
METHODS
Immunophenotyping using CyTOF, single cell RNA sequencing (scRNA-seq) and T cell receptor (TCR) sequencing was performed on peripheral blood and intestinal tissue samples from refractory CD patients who underwent SCT. The stem cell graft from these patients was analyzed using flow cytometry and functionally interrogated using a murine model for engraftment.
RESULTS
Our study revealed a remodeling of intestinal macrophages capable of supporting mucosal healing that was independently validated using multimodal studies of immune reconstitution events including CyTOF and scRNA-seq. Functional interrogation of hematopoietic stem cells (HSCs) using a xenograft model demonstrated that HSCs shape the timing of immune reconstitution, the selected reconstitution of specific cell lineages and potentially the clinical efficacy of SCT.
CONCLUSIONS
These studies indicate that SCT serves as a myeloid-directed cellular therapy re-establishing homeostatic intestinal macrophages that support intestinal healing and suggest refractory CD evolves from impairment of restorative functions in myeloid cells. Furthermore, we report heterogeneity among HSCs from CD patients which may drive SCT outcomes and suggests an unrecognized impact of CD pathophysiology on HSC in the marrow niche.
PubMed: 38895305
DOI: 10.1101/2024.05.30.596699 -
International Journal of Molecular... May 2024Mucosal-associated invariant T (MAIT) cells, a subset of Vα7.2+ T cells, are a crucial link between innate and adaptive immunity, responding to various stimuli through...
Mucosal-associated invariant T (MAIT) cells, a subset of Vα7.2+ T cells, are a crucial link between innate and adaptive immunity, responding to various stimuli through TCR-dependent and independent pathways. We investigated the responses of MAIT cells and Vα7.2+/CD161- T cells to different stimuli and evaluated the effects of Cyclosporin A (CsA) and Vitamin D3 (VitD). Peripheral blood mononuclear cells (PBMCs) from healthy donors were stimulated with various agents (PMA/Ionomycin, 5-OP-RU, 5-OP-RU/IL-12/IL-33) with or without CsA and VitD. Flow cytometric analysis assessed surface markers and intracellular cytokine production. Under steady-state conditions, MAIT cells displayed elevated expression of CCR6 and IL-13. They showed upregulated activation and exhaustion markers after activation, producing IFNγ, TNFα, and TNFα/GzB. CsA significantly inhibited MAIT cell activation and cytokine production. Conversely, Vα7.2+/CD161- T cells exhibited distinct responses, showing negligible responses to 5-OP-RU ligand but increased cytokine production upon PMA stimulation. Our study underscores the distinct nature of MAIT cells compared to Vα7.2+/CD161- T cells, which resemble conventional T cells. CsA emerges as a potent immunosuppressive agent, inhibiting proinflammatory cytokine production in MAIT cells. At the same time, VitD supports MAIT cell activation and IL-13 production, shedding light on potential therapeutic avenues for immune modulation.
Topics: Humans; Mucosal-Associated Invariant T Cells; NK Cell Lectin-Like Receptor Subfamily B; Lymphocyte Activation; Immunologic Factors; Cytokines; Cyclosporine; Cholecalciferol; Leukocytes, Mononuclear
PubMed: 38892082
DOI: 10.3390/ijms25115895 -
Frontiers in Veterinary Science 2024The objective of this study is to review different methods to screen for the optimal model for preventing and treating chicken glandular and muscular gastritis syndrome....
The objective of this study is to review different methods to screen for the optimal model for preventing and treating chicken glandular and muscular gastritis syndrome. Twenty-four 40-day-old specific pathogen-free (SPF) chickens were randomly allocated into four groups ( = 6): polyethylene glycol + ammonium chloride group (M1 group), acetic acid + rhubarb group (M2 group), polyethylene glycol + rhubarb group (M3 group), and control group. The control group had free access to water, while the remaining groups received different doses of molding reagents added to their drinking water. The animal models were assessed based on clinical manifestations, histopathology findings, serological analysis, and composition of intestinal microbiota to establish an optimal approach for constructing an avian model of glandular and muscular gastritis. The SPF chickens in each model group exhibited typical symptoms of glandular and muscular gastritis, poor spirit, yellow loose stools with undigested feed, and enlargement and ulceration of the glandular and muscular stomach. Among these groups, the M3 group had the highest incidence rate of 100%. Compared to the control group, the body weight and body temperature of the chicken in the three model groups were reduced, and the glandular and muscular stomachs and duodenum showed different degrees of bleeding, mucosal abscission, and other pathological injuries. Additionally, the levels of serum IL-2 and α-amylase activity decreased while the content of IL-4 increased. After conducting 16s rDNA sequencing, it was observed that the abundance of , and was significantly increased in the model group compared to the control group. Conversely, there was a notable decrease in the levels of and , which are speculated to be associated with arachidonic acid metabolism, the NF-κB signaling pathway, and TNF signaling pathways. The combination of polyethylene glycol and rhubarb emerged as the most effective method for establishing the glandular and muscular gastritis model in SPF chickens. This constructed chicken model displayed distinct signs of damage to the glandular and muscular stomach, inflammatory response, and disturbance in the intestinal flora, thereby providing a foundation for future research on the prevention and treatment of this syndrome.
PubMed: 38887537
DOI: 10.3389/fvets.2024.1343768 -
Frontiers in Microbiology 2024Infection with SARS-CoV-2 begins in the upper respiratory tract and can trigger the production of mucosal spike-specific secretory IgA (sIgA), which provides protection...
INTRODUCTION
Infection with SARS-CoV-2 begins in the upper respiratory tract and can trigger the production of mucosal spike-specific secretory IgA (sIgA), which provides protection against reinfection. It has been recognized that individuals with high level of nasal spike-specific IgA have a lower risk of reinfection. However, mucosal spike-specific sIgA wanes over time, and different individuals may have various level of spike-specific sIgA and descending kinetics, leading to individual differences in susceptibility to reinfection. A method for detecting spike-specific sIgA in the nasal passage would be valuable for predicting the risk of reinfection so that people at risk can have better preparedness.
METHODS
In this study, we describe the development of a colloidal gold-based immunochromatographic (ICT) strip for detecting SARS-CoV-2 Omicron spike-specific sIgA in nasal mucosal lining fluids (NMLFs).
RESULTS
The ICT strip was designed to detect 0.125 μg or more spike-specific sIgA in 80 μL of NMLFs collected using a nasal swab. Purified nasal sIgA samples from individuals who recently recovered from an Omicron BA.5 infection were used to demonstrate that this ICT strip can specifically detect spike-specific sIgA. The signal levels positively correlated with neutralizing activities against XBB. Subsequent analysis revealed that people with low or undetectable levels of spike-specific sIgA in the nasal passage were more susceptible to SARS-CoV-2 reinfection.
CONCLUSIONS
This nasal spike-specific sIgA ICT strip provides a non-invasive, rapid, and convenient method to assess the risk of reinfection for achieving precision preparedness.
PubMed: 38881666
DOI: 10.3389/fmicb.2024.1386891