scholarly journals Modulation of Intestinal Goblet Cell Function during Infection by an Attaching and Effacing Bacterial Pathogen

2007 ◽  
Vol 76 (2) ◽  
pp. 796-811 ◽  
Author(s):  
Kirk S. B. Bergstrom ◽  
Julian A. Guttman ◽  
Mohammad Rumi ◽  
Caixia Ma ◽  
Saied Bouzari ◽  
...  
Keyword(s):  
Immune System ◽  
Goblet Cell ◽  
Cell Function ◽  
Bacterial Pathogen ◽  
Goblet Cells ◽  
Cell Depletion ◽  
Intestinal Lumen ◽  
Host Immune System ◽  
Immunocompetent Mice

ABSTRACT The attaching and effacing (A/E) bacterial pathogens enteropathogenic Escherichia coli and enterohemorrhagic E. coli and the related mouse pathogen Citrobacter rodentium colonize their hosts' intestines by infecting the apical surfaces of enterocytes, subverting their function, and they ultimately cause diarrhea. Surprisingly, little is known about the interactions of these organisms with goblet cells, which are specialized epithelial cells that secrete the protective molecules Muc2 and trefoil factor 3 (Tff3) into the intestinal lumen. C. rodentium infection leads to dramatic goblet cell depletion within the infected colon, yet it is not clear whether C. rodentium infects goblet cells or if this pathology is pathogen or host mediated. As determined by immunostaining and PCR, both the number of goblet cells and the expression of genes encoding Muc2 and Tff3 were significantly reduced by day 10 postinfection. While electron microscopy and immunostaining revealed that C. rodentium directly infected a fraction of colonic goblet cells, C. rodentium localization did not correlate with goblet cell depletion. To assess the role of the host immune system in these changes, Rag1 knockout (KO) (T- and B-cell-deficient) mice were infected with C. rodentium. Rag1 KO mice did not exhibit the reduction in the number of goblet cells or in mediator (Muc2 and Tff3) expression observed in infected immunocompetent mice. However, reconstitution of Rag1 KO mice with T and B lymphocytes from C57BL/6 mice restored the goblet cell depletion phenotype during C. rodentium infection. In conclusion, these studies demonstrated that while colonic goblet cells can be subject to direct infection and potential subversion by A/E pathogens in vivo, it is the host immune system that primarily modulates the function of these cells during infection.

scholarly journals Biofilm formation in the lung contributes to virulence and drug tolerance of Mycobacterium tuberculosis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Poushali Chakraborty ◽  
Sapna Bajeli ◽  
Deepak Kaushal ◽  
Bishan Dass Radotra ◽  
Ashwani Kumar
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Immune System ◽  
Biofilm Formation ◽  
Antimycobacterial Activity ◽  
Drug Tolerance ◽  
Host Immune System ◽  
Tissue Sections ◽  
Slow Growing

AbstractTuberculosis is a chronic disease that displays several features commonly associated with biofilm-associated infections: immune system evasion, antibiotic treatment failures, and recurrence of infection. However, although Mycobacterium tuberculosis (Mtb) can form cellulose-containing biofilms in vitro, it remains unclear whether biofilms are formed during infection in vivo. Here, we demonstrate the formation of Mtb biofilms in animal models of infection and in patients, and that biofilm formation can contribute to drug tolerance. First, we show that cellulose is also a structural component of the extracellular matrix of in vitro biofilms of fast and slow-growing nontuberculous mycobacteria. Then, we use cellulose as a biomarker to detect Mtb biofilms in the lungs of experimentally infected mice and non-human primates, as well as in lung tissue sections obtained from patients with tuberculosis. Mtb strains defective in biofilm formation are attenuated for survival in mice, suggesting that biofilms protect bacilli from the host immune system. Furthermore, the administration of nebulized cellulase enhances the antimycobacterial activity of isoniazid and rifampicin in infected mice, supporting a role for biofilms in phenotypic drug tolerance. Our findings thus indicate that Mtb biofilms are relevant to human tuberculosis.

scholarly journals Glutamate triggers the expression of functional ionotropic and metabotropic glutamate receptors in mast cells

2020 ◽  
Author(s):  
Md Abdul Alim ◽  
Mirjana Grujic ◽  
Paul W. Ackerman ◽  
Per Kristiansson ◽  
Pernilla Eliasson ◽  
...  
Keyword(s):  
Mast Cell ◽  
Immune System ◽  
Mast Cells ◽  
Glutamate Receptors ◽  
Glutamate Receptor ◽  
Metabotropic Glutamate Receptors ◽  
Cell Function ◽  
Metabotropic Glutamate ◽  
Protein Levels

Abstract Mast cells are emerging as players in the communication between peripheral nerve endings and cells of the immune system. However, it is not clear the mechanism by which mast cells communicate with peripheral nerves. We previously found that mast cells located within healing tendons can express glutamate receptors, raising the possibility that mast cells may be sensitive to glutamate signaling. To evaluate this hypothesis, we stimulated primary mast cells with glutamate and showed that glutamate induced the profound upregulation of a panel of glutamate receptors of both the ionotropic type (NMDAR1, NMDAR2A, and NMDAR2B) and the metabotropic type (mGluR2 and mGluR7) at both the mRNA and protein levels. The binding of glutamate to glutamate receptors on the mast cell surface was confirmed. Further, glutamate had extensive effects on gene expression in the mast cells, including the upregulation of pro-inflammatory components such as IL-6 and CCL2. Glutamate also induced the upregulation of transcription factors, including Egr2, Egr3 and, in particular, FosB. The extensive induction of FosB was confirmed by immunofluorescence assessment. Glutamate receptor antagonists abrogated the responses of the mast cells to glutamate, supporting the supposition of a functional glutamate–glutamate receptor axis in mast cells. Finally, we provide in vivo evidence supporting a functional glutamate–glutamate receptor axis in the mast cells of injured tendons. Together, these findings establish glutamate as an effector of mast cell function, thereby introducing a novel principle for how cells in the immune system can communicate with nerve cells.

Use of immunological manipulations in studying genetically controlled responses to Leishmania donovani infection in mice

Parasitology ◽  
1984 ◽  
Vol 88 (4) ◽  
pp. 677-679 ◽  
Author(s):  
Jenefer M. Blackwell
Keyword(s):  
Immune System ◽  
Leishmania Donovani ◽  
Inbred Mouse ◽  
Parasitic Infection ◽  
Preceding Paper ◽  
Mouse Strains ◽  
Host Immune System ◽  
Inbred Mouse Strains

In the preceding paper Howard (p. 665) has given a very elegant presentation on ways in which the host immune system may be manipulated to provide valuable information about immunoregulation of parasitic infection in vivo. In our laboratory we have used some of the same manoeuvres to study immunoregulation of genetically controlled responses to Leishmania donovani infection in inbred mouse strains (Ulczak & Blackwell, 1983; Crocker, Blackwell & Bradley, 1984). As has been Howard's experience, the results obtained have not always been as one might have predicted at the outset.

Vaccination with Leukemia Cells Expressing Cell-Surface-Associated GM-CSF Blocks Leukemia Induction in Immunocompetent Mice.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2531-2531
Author(s):  
Xiaoyang Ling ◽  
Yan Wang ◽  
Ralph B. Arlinghaus
Keyword(s):  
Immune System ◽  
Cell Surface ◽  
Immune Tolerance ◽  
Leukemia Cells ◽  
Host Immune System ◽  
Over Expression ◽  
Gm Csf ◽  
Significant Difference ◽  
Specific Antigens ◽  
Immunocompetent Mice

Abstract The fundamental basis for immunotherapy of leukemia is that leukemia cells express specific antigens that are not expressed by normal hematopoietic cells. However, the host immune system appears to be tolerant of leukemia cells. To overcome this immune tolerance, we transduced WEHI-3B mouse monocyte leukemia cells (1) with a transmembrane form of GM-CSF (tmGM-CSF). The tmGM-CSF was constructed using the pDisplay vector for cell-surface targeting (Invitrogen) into the pLOX lentivirus gene transfer vector (2). After infection of WEHI-3B cells with a recombinant lentivirus encoding tmGM-CSF, nearly all the transduced cells expressed tmGM-CSF on the cell-surface, as determined by flow cytometry analysis using anti-GM-CSF. To determine whether vaccination with tmGM-CSF expressing WEHI-3B cells would prevent leukemia formation, immunocompetent BALB/c mice were immunized with lethally-irradiated WEHI-3B cells (106, 3 times 7 day intervals), which express tmGM-CSF, prior to challenging vaccinated mice with WEHI-3B cells (5x104) that express GFP as a marker. 100% of vaccinated mice were protected from leukemia. Non-vaccinated mice succumbed to leukemia within 50–55 days. Vaccination of mice with lethally-irradiated WEHI-3B cells expressing CD40L protected 80% of the mice from leukemia. In contrast, mice immunized with lethally-irradiated WEHI-3B/GFP cells lacking tmGM-CSF were not protected. Mice vaccinated three times at 5,12, 19 days after challenge with WEHI-3B/GFP cells had a significant increase in survival in that 60% of mice were alive and healthy at 16 days (to this date) after all control non-vaccinated mice had died. Similar vaccine studies were performed with BCR-ABL (b3a2)+ 32D cells (106) in immunocompetent C3H/HeJ mice (3). These mice die of leukemia within 35 days. After infection of BCR-ABL+ 32D cells with the lentivirus encoding tmGM-CSF/GFP, tmGM-CSF was expressed on the cell-surface. The C3H/HeJ mice challenged with BCR-ABL+32D/GFP cells (106) showed a significant level of protection by vaccination with lethally-irradiated tmGM-CSF+ 32D BCR-ABL cells (106, 2 times at 7 day intervals); 40% of the vaccinated mice remained healthy; all non-vaccinated mice died of leukemia. There was a significant difference in survival (P=0.03) between the vaccinated and non-vaccinated groups. Interestingly, the spleens of vaccinated C3H/HeJ mice that died of leukemia at the same time as non-vaccinated mice approached normal size whereas non-vaccinated mice had enlarged spleens. Our findings suggest that over-expression of cell-surface tmGM-CSF in leukemia cells can overcome immune tolerance, allowing the immune system to efficiently recognize and destroy the leukemia cells, providing extended survival of vaccinated mice. Because significant protection from death was achieved by vaccination after challenge with leukemia cells, tmGM-CSF expression in leukemia cells has potential as a therapeutic strategy for treatment of leukemia.

Effect of Adenoviral Early Genes and the Host Immune System on In Vivo Pancreatic Gene Transfer in the Mouse

Pancreas ◽  
1997 ◽  
Vol 15 (3) ◽  
pp. 236-245 ◽  
Author(s):  
Steven J. McClane ◽  
Thomas E. Hamilton ◽  
Ronald P. DeMatteo ◽  
Charlotte Burke ◽  
Steven E. Raper
Keyword(s):  
Immune System ◽  
Gene Transfer ◽  
Host Immune System ◽  
Early Genes

scholarly journals Modulation of Conjunctival Goblet Cell Function by Inflammatory Cytokines

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
L. Contreras-Ruiz ◽  
A. Ghosh-Mitra ◽  
M. A. Shatos ◽  
D. A. Dartt ◽  
S. Masli
Keyword(s):  
Sjögren’S Syndrome ◽  
Inflammatory Cytokines ◽  
Goblet Cell ◽  
Ocular Surface ◽  
Cell Function ◽  
Sjögren's Syndrome ◽  
Goblet Cells ◽  
Sjogren’S Syndrome ◽  
Sjogren's Syndrome ◽  
Sjögren‘S Syndrome

Ocular surface inflammation associated with Sjögren’s syndrome is characterized by a loss of secretory function and alteration in numbers of mucin secreting goblet cells. Such changes are a prominent feature of ocular surface inflammatory diseases and are attributed to inflammation; however, the exact effect of the inflammatory cytokines on conjunctival goblet cell function remains largely unknown. In this study, we developed a primary culture of mouse goblet cells from conjunctival tissue and evaluated the effects on their function by inflammatory cytokines detected in the conjunctiva of mouse model of Sjögren’s syndrome (Thrombospondin-1 deficient mice). We found that apoptosis of goblet cells was primarily induced by TNF-αand IFN-γ. These two cytokines also inhibited mucin secretion by goblet cells in response to cholinergic stimulation, whereas IL-6 enhanced such secretion. No changes in secretory response were detected in the presence of IL-13 or IL-17. Goblet cells proliferated to varying degrees in response to all the tested cytokines with the greatest response to IL-13 followed by IL-6. Our results therefore reveal that inflammatory cytokines expressed in the conjunctiva during an ocular surface disease directly disrupt conjunctival goblet cell functions, compromising the protective function of tears, thereby contributing to ocular surface damage.

scholarly journals Antitumor and immunomodulatory activity of Inonotus obliquus

2017 ◽  
Vol 63 (2) ◽  
pp. 48-58 ◽  
Author(s):  
Justyna Staniszewska ◽  
Marcin Szymański ◽  
Ewa Ignatowicz
Keyword(s):  
Immune System ◽  
Tumor Cells ◽  
Good Alternative ◽  
Immunomodulatory Activity ◽  
Host Immune System ◽  
Protein Synthesis Inhibition ◽  
Inonotus Obliquus ◽  
Different Types

SummaryThe article presents the antitumor and immunomodulatory activity of compounds and extracts fromInonotus obliquus.Polysaccharides isolated from sclerotium have a direct antitumor effect due to protein synthesis inhibition in tumor cells. Polysaccharides derived from the mycelium function by activating the immune system. Due to the limited toxicity of these substances, both extracts as well as isolated and purified chemicals may be a good alternative to current chemotherapy and play a role in cancer prevention.In vitroexperiments have shown the inhibition of inflammation with the influence of action ofI. obliquusextracts; however,in vivoexperiments on animals implanted with tumor cells of different types have shown the activation of the host immune system. This led to decrease in tumor mass and prolonged survival. The immunomodulatory mechanism of action is complex and it seems that stimulation of macrophages and induction of apoptosis in cancer cells is of great importance.

scholarly journals Mycobacterium tuberculosis Transcriptome Profiling in Mice with Genetically Different Susceptibility to Tuberculosis

Acta Naturae ◽  
2013 ◽  
Vol 5 (2) ◽  
pp. 62-69 ◽  
Author(s):  
T. A. Skvortsov ◽  
D. V. Ignatov ◽  
K. B. Majorov ◽  
A. S. Apt ◽  
T. L. Azhikina
Keyword(s):  
Transcriptional Profiling ◽  
Anaerobic Respiration ◽  
Bacterial Pathogen ◽  
Transcriptome Profiling ◽  
Relevant Information ◽  
Mouse Strains ◽  
Host Immune System ◽  
Cell Processes ◽  
Upregulated Genes

Whole transcriptome profiling is now almost routinely used in various fields of biology, including microbiology. In vivo transcriptome studies usually provide relevant information about the biological processes in the organism and thus are indispensable for the formulation of hypotheses, testing, and correcting. In this study, we describe the results of genome-wide transcriptional profiling of the major human bacterial pathogen M. tuberculosis during its persistence in lungs. Two mouse strains differing in their susceptibility to tuberculosis were used for experimental infection with M. tuberculosis. Mycobacterial transcriptomes obtained from the infected tissues of the mice at two different time points were analyzed by deep sequencing and compared. It was hypothesized that the changes in the M. tuberculosis transcriptome may attest to the activation of the metabolism of lipids and amino acids, transition to anaerobic respiration, and increased expression of the factors modulating the immune response. A total of 209 genes were determined whose expression increased with disease progression in both host strains (commonly upregulated genes, CUG). Among them, the genes related to the functional categories of lipid metabolism, cell wall, and cell processes are of great interest. It was assumed that the products of these genes are involved in M. tuberculosis adaptation to the host immune system defense, thus being potential targets for drug development.

scholarly journals CRISPR/Cas9-loaded stealth liposomes effectively cleared established HPV16-driven tumours in syngeneic mice

PLoS ONE ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. e0223288
Author(s):  
Luqman Jubair ◽  
Alfred K. Lam ◽  
Sora Fallaha ◽  
Nigel A. J. McMillan
Keyword(s):  
Cell Death ◽  
Gene Editing ◽  
Cancer Cell Line ◽  
Host Immune System ◽  
Stealth Liposomes ◽  
Efficient Delivery ◽  
Significant Toxicity ◽  
Immunocompetent Mice ◽  
First Time

Gene-editing has raised the possibility of being able to treat or cure cancers, but key challenges remain, including efficient delivery, in vivo efficacy, and its safety profile. Ideal targets for cancer therapy are oncogenes, that when edited, cause cell death. Here, we show, using the human papillomavirus (HPV) type 16 cancer cell line TC1, that CRISPR/Cas9 targeting the E7 oncogene and packaged in PEGylated liposomes cleared established tumours in immunocompetent mice. Treatment caused no significant toxicity in the spleen or liver. An ideal therapeutic outcome would be the induction of an immunogenic cell death (ICD), such that recurrent tumours would be eliminated by the host immune system. We show here for the first time that CRISPR/Cas9-mediated cell death via targeting E7 did not result in ICD. Overall, our data show that in vivo CRISPR/Cas targeting of oncogenes is an effective treatment approach for cancer.

scholarly journals Rescuing the Host Immune System by Targeting the Immune Evasion Complex ORF8-IRF3 in SARS-CoV-2 Infection with Natural Products Using Molecular Modeling Approaches

2021 ◽  
Vol 19 (1) ◽  
pp. 112
Author(s):  
Aqel Albutti
Keyword(s):  
Immune System ◽  
Immune Evasion ◽  
Simulation Analysis ◽  
Dynamic Properties ◽  
Natural Compounds ◽  
Host Immune System ◽  
Structural Dynamic ◽  
Novel Drugs

The perennial emergence of SARS-CoV-2 and its new variants causing upper respiratory complexities since December 2019 has aggravated the pandemic situation around the world. SARS-CoV-2 encodes several proteins among which ORF8 is a novel factor that is unique to SARS-CoV-2 only and is reported to help the virus in disease severity and immune evasion. ORF8-IRF3 complex induces endoplasmic reticulum stress, thus helps in the evasion of immune response. Consequently, targeting the ORF8-IRF3 complex is considered as a prime target for the discovery of novel drugs against SARS-CoV-2. In this regard, computational methods are of great interest to fast track the identification and development of novel drugs. Virtual screening of South African Natural Compounds Database (SANCDB), followed by docking and molecular dynamics (MD) simulation analysis, were performed to determine novel natural compounds. Computational molecular search and rescoring of the SANCDB database followed by induced-fit docking (IFD) protocol identified Quercetin 3-O-(6″-galloyl)-beta-D-galactopyranoside (SANC00850), Tribuloside (SANC01050), and Rutin (SANC00867) are the best scoring compounds. Structural-dynamic properties assessment revealed that these three compounds have stable dynamics, compactness, and a higher number of hydrogen bonds. For validation, we used MM/GBSA, in silico bioactivity estimation and dissociation constant (KD) approaches, which revealed that these compounds are the more potent inhibitors of the ORF8-IRF3 complex and would rescue the host immune system potentially. These compounds need further in vitro and in vivo validations to be used as therapeutics against SARS-CoV-2 to rescue the host immune system during COVID-19 infection.

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